Aplicações Terapêuticas de Fitoterápicossintéticosbiomedicamentos No Câncer Bucal Uma Atualização

European Journal of Pharmacology 890 (2021) 173657
Contents lists available at ScienceDirect
European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar
Review
Therapeutic applications of herbal/synthetic/bio-drug in oral cancer:

An update
Seyed Ali Mosaddad a, Kimia Beigi a, Tayebeh Doroodizadeh b, Maral Haghnegahdar c,
Farzaneh Golfeshan d, Reza Ranjbar e, Hamid Tebyanian e, *
a
Student Research Committee, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
b
Department of Pediatric Dentistry, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
c
Department of Pharmacology & Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
d
Orthodontic Research Center, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
e
Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O A B S T R A C T
Keywords: Oral cancer, as one of the most prevalent and invasive cancers that invade local tissue, can cause metastasis, and
Oral cancer have high mortality. In 2018, around 355,000 worldwide oral cancers occurred and resulted in 177,000 deaths.
Herbal drug Estimates for the year 2020 include about 53,260 new cases added to previous year’s cases, and the estimated
Synthetic drug
death toll from this cancer in 2020 is about 10,750 deaths more than previous years. Despite recent advances in
Bio-drug
Treatment
cancer diagnosis and treatment, unfortunately, 50% of people with cancer cannot be cured. Of course, it should
be remembered that the type of treatment used greatly influences patient recovery. There are not many choices
when it comes to treating oral cancer. Research efforts focusing on the discovery and evolution of innovative
therapeutic approaches for oral cancer are essential. Such traditional methods of treating this type of cancer like
surgery and chemotherapy, have evolved dramatically during the past thirty to forty years, but they continue to
cause panic among patients due to their side effects. Therefore, it is necessary to study and use drugs that are less
risky for the patient as well as to provide solutions to reduce chemotherapy-induced adverse events that prevent
many therapeutic risks. As mentioned above, this study examines low-risk therapies such as herbal remedies,
biological drugs, and synthetic drugs in the hope that they will be useful to physicians, researchers, and scientists
around the world.
1. Introduction salivary gland carcinomas, sarcomas, and lymphomas, and the remain
ing 1% are metastatic cancers of the breast, prostate, and kidneys (Little
1.1. Statistics et al., 2008). The incidence of oral cancer and the resulting deaths vary
across the globe. The highest incidence of oral cancer is in developing
A relatively large number of people suffer from oral cancer, which is countries including India, Pakistan, Bangladesh, Hong Kong, Singapore,
one of the top ten life-threatening diseases around the world (D’Silva and the Philippines (Garg and Chaturvedi, 2016; Iamaroon et al., 2004).
and Gutkind, 2019). They include tumors of the lips, tongue, gums, In Southeast Asia, and especially in India, oral cancers are the most
palms of the mouth, hard and soft palate, tonsils, salivary glands, common cancers and account for 35% of cancer cases among male pa
oropharynx, nasopharynx, and hypopharynx. At least 90% of head and tients and 18% among female patients (Wünsch-Filho, 2002) (Fig. 1).
neck cancers (i.e. more than 600,000 new cancers annually) are squa Among male patients, oral cancer is the sixth most prevalent cancer, and
mous cell carcinoma (SCC) (Ferlay et al., 2019; Leemans et al., 2018). among female patients, it is the 12th most prevalent one (Greenberg
Studies show that the most frequent site of SCC in the head and neck area et al., 2008). Racially, American blacks are more likely to contract oral
is the oral cavity. Among these, the lips are the most common (Ettinger and pharyngeal cancer than white people (Gupta et al., 2016). Of all the
et al., 2019; Siegel et al., 2019). Over 90% of oral cancer cases are a type factors that may be involved in developing oral cancer, the most influ
of SCC (Canto and Devesa, 2002). Also, about 9% of cancers include ential is age because nearly 95% of the cases take place among those
* Corresponding author.
E-mail address: [email protected] (H. Tebyanian).
https://doi.org/10.1016/j.ejphar.2020.173657
Received 30 June 2020; Received in revised form 1 October 2020; Accepted 20 October 2020
Available online 21 October 2020
0014-2999/© 2020 Elsevier B.V. All rights reserved.
S.A. Mosaddad et al. European Journal of Pharmacology 890 (2021) 173657
over 40, who are on average 65 years old (Dhanuthai et al., 2018). factors, such as exposure to ultraviolet radiation and immune disorders
(such as HIV infection and organ transplantation), account for 10% of
these cases, especially for lip cancer. Human papillomavirus infection
1.2. Risk factors for oral cancer can be seen in up to 30% of cases (Rhodus, 2005). Plummer–Vinson
syndrome and vitamin A deficiency also increases the likelihood of oral
Among the various items that lead to oral and pharyngeal cancer, and pharyngeal cancer. Other reasons, such as arsenic compounds used
tobacco and alcohol are the best known. Those who smoke are seven in the treatment of syphilis, nutritional deficiencies, exposure to com
times more likely to have cancer (Cardesa et al., 2017). The relative risk pounds such as wood and metal are less likely to cause cancer (Jeihooni
of developing cancer is 6 times higher for people who use too much et al., 2019).
alcohol, and 38 times more for patients who use alcohol and tobacco
together (Huang and O’Sullivan, 2017; Regezi et al., 2016). Other
Fig. 1. Estimated new cancer cases (left column) and deaths (right column) by sex, United States, 2020.
2
1.3. General clinical features of oral cancer disease, the invasion of the bone and lymph nodes of the neck, and
adhesion to the carotid artery (Ali et al., 2016). Chest x-rays and liver
The clinical features of carcinoma vary in the mucosal surfaces of function tests are performed to accurately assess metastasis (Rohde
oral cancer. The tumor may be seen in various forms of ulcers, promi et al., 2017).
nent mass (fungal, papillary, wart), white plaque, red plaque, or a
combination of white and red plaque (Hashim et al., 2019). Many pri
mary cancers of the mouth are asymptomatic, whereas advanced lesions 1.7. Prognosis of oral cancer
are often ulcerated and with prominent and rigid margins. Pain is often
absent until the last stages of the disease (Smitha et al., 2019; Sridharan The prognosis depends on the three main factors of the lesion, the
et al., 2019). location of the tumor, the existence or absence of metastasis to the
lymph nodes, and the size of the tumor (Cardesa et al., 2017). Metastasis
1.4. Lip cancers to the neck lymph nodes is prevalent but distant metastasis is rare. In the
case of distant metastasis, the liver and bones are places that are usually
Locally, as noted, oral cancer occurs most frequently in the lip. Lip involved. Metastasis usually occurs in those who have advanced or
cancers are almost without exception SCC. Lip cancer is often a disease localized cancer or recurrent disease. Oral cancers that occur in the back
of light-skinned older men and, in most cases, affects the lower lip of the oral cavity, throat, and the lower part have a poorer prognosis
vermilion. Risk factors for developing lip cancer include sun exposure, because these tumors are usually diagnosed in advanced stages and are
specific occupations such as agriculture, socioeconomic status, and more likely to invade lymph nodes when diagnosed (Mishra, 2019).
smoking habits, and pipes (Levine and Stillman-Lowe, 2019; Peres et al., Researchers have shown that 40% of tumors present in the retromolar
2019). trigone region of the cheek have a chance of recovery, while 17% of
tumors in the middle third of the cheek and only 10% of the posterior
1.5. Intra-oral cancers one-third of the cheek tumors have a chance of recovery (Cardesa et al.,
2017). Unfortunately, for most oral cancers diagnosis occurs too late
High-risk sites for cancer inside the mouth are the inner mucosa of when the disease is advanced and the patient is experiencing the
the mouth, the posterior side of the tongue, the oral palm, and the soft symptoms of the disease (Regezi et al., 2016), which greatly reduces a
palate (Bewley and Farwell, 2017; Johnson et al., 2017). As the most person’s chance of recovery (Cardesa et al., 2017).
common intra-oral site, tongue cancer usually develops in men in their
sixties and seventies, but it can also occur at younger ages. Tongue le
sions often have aggressive behavior (Zidar et al., 2018). The tumor is 1.8. Treatment options for oral cancer
painless in the early stages and may appear as white or red plaque, or
small bumps, but becomes ulcerated if left untreated. The resulting Currently, the main treatments known in oral cancer are surgery,
wound becomes rigid and the tongue becomes immobilized. The main radiation, and chemotherapy (Ragos et al., 2018). Many people who
symptoms, in this case, are pain and difficulty in speech and swallowing suffer from cancer go through radiation therapy or chemotherapy and
(Ord and Lubek, 2017). Extension to the lymph nodes depends on the anticancer drugs could prove beneficial to them (DeSantis et al., 2014).
primary location of the tumor. Tumors on the tip of the tongue invade Nevertheless, due to the toxic effects of anticancer drugs on normal cells
the subcutaneous part of the chin and jugular lymph nodes, and the and tissues, they have numerous side effects including nausea, vomiting,
posterior tumors invade the submandibular and jugulodigastric lymph anorexia, diarrhea, oral mucositis, and numbness. Such negative effects
nodes (Prabhu et al., 2017). usually endanger the quality of life for the patients, which sometimes
The oral floor is the second most common intra-oral location for makes radiation or chemotherapy difficult to continue (Ohnishi and
cancerous changes. Carcinomas occur in this area in older men, espe Takeda, 2015). Although many useful approaches have been formulated
cially smokers and alcoholics. Tumors of this location invade adjacent to either stop these side effects from happening or improve them, these
tissues and involve the submandibular and jugular lymph nodes (Regezi approaches are inadequate (Hershman et al., 2014; Langston et al.,
et al., 2016). Buccal and gingival mucosal involvement is also common, 2013; Lee and Shukla, 2005; Ohnishi and Takeda, 2015). Thus, a
especially in areas where there are specific habits, such as chewing to different or new strategy is needed. In this review article, we aim to
bacco (Ragos et al., 2018). evaluate three different types of drug therapy for oral cancer, along with
the advantages and disadvantages of each, by presenting solutions to
1.6. Diagnosis of oral cancer reduce the side effects of their use to increase the effectiveness of the
treatment.
The diagnosis of suspected oral cancer is made by assessing the pa
tient’s demographic characteristics and by examining specific habits, 2. Method
particularly tobacco and alcohol use, and other triggering factors that
may contribute to oral cancer (Scannapieco and Cantos, 2016). A A non-systematic review of present issues in available herbal, syn
complete history should also include a history of oral health status and thetic, and bio-drugs for treating oral cancers was done By searching the
exposure to any other carcinogens. Family history should also be PubMed and the keywords of oral cancer (141,208 results; 11,297
reviewed to determine if any syndromes may increase the chances of clinical trials), oral cancer treatment (89,237 results; 10,927 clinical
developing oral cancer (Leemans et al., 2018). A complete examination trials), cancer herbal drugs (6790 results; 526 clinical trials), cancer
of the head and neck is also performed to closely examine the location synthetic drugs (3798 results; 84 clinical trials), cancer drugs (212,417
and spread of the primary tumor and identify metastases. It should be results; 13,410 clinical trials), and anticancer drugs (41,835 results;
noted that cancers in the early stages are usually red or white plaque and 1124 clinical trials). Papers (only in English) were included according to
non-injured. More advanced cancers are ulcerative and invasive, or clinical use and practice-changing research, some translational articles,
fungal and prominent, or both (Myers and Hanna, 2016). Cancer can and comprehensive reviews related to the last 5 years were also priori
occur within pre-malignant lesions such as leukoplakia or erythroplakia tized. Related papers were recognized by searching the authors’ files as
(Huang and O’Sullivan, 2017). Histologic confirmation of oral cancer well as the review of other articles and their references. Unpublished
diagnosis is required before any treatment (Yoneda et al., 2017). Oral articles provided for a conference were found by searching libraries and
and pharyngeal neoplasms are usually diagnosed by clinical examina abstract books. We also reviewed their references. The ultimate refer
tion and biopsy, and radiography is needed to evaluate the spread of the ence list was formed based on our objectives.
3
3. Herbal drugs 3.1. Curcumin
Human beings initially provided the necessary medicines from na The human diet consists of a set of plant polyphenols. Curcumin
ture, especially herbs, to cure their pains and diseases. In addition to (Diferuloylmethane) is a compound of phenol derived from the rhizome
producing good effects, chemical drugs have some side effects that may of Curcuma spp. (Yuan et al., 2017) with various beneficial pharmaco
last for life, and even in some cases, be passed on to the next generation. logical features such as anti-cancer, anti-inflammatory, and anti-aging
However, the side effects of herbal remedies are less, and in many cases, (Liu et al., 2020). Research shows that curcumin inhibits the growth
very low and uncomplicated (Kocaadam and Sanlier, 2017). Since of cancer cells by apoptosis and preventing cancer cells from prolifer
almost 50% of available medicines come from plants, natural resources, ating (Giordano and Tommonaro, 2019). The reason curcumin causes
especially herbs, can be investigated to find effective medicines for apoptosis is the production of cytochrome C and reactive oxygen species
cancer treatment. The primary goals of using herbal remedies in cancer and their effect on p53 protein, as well as activating intracellular signals
treatment are the primary prevention of cancer by creating an unde responsible for DNA damage and cell growth arrest (Khan, 2019). Cur
sirable environment for cancer cell growth, preventing cancer recur cumin can have an inhibitory effect on cancers of the colon, pancreas,
rence, enhancing the immune system, and reducing the side effects of stomach, and prostate. Since free radicals and the toxic by-products of
using new treatments like chemotherapy and radiotherapy (Steigerwalt oxidative stress are greatly influential in the beginning stages of cancer,
et al., 2012; Wang et al., 2020b). The combination of chemotherapeutic compounds that have antioxidant effects can be useful in preventing
agents is now universally applied to different types of cancer. Besides the cancer. Curcumin has the effect of trapping potent free radicals and can
advantage of combination therapy that is lowering the doses of each have an inhibitory role in the onset of cancer. Numerous cellular and
drug that can result in decreased resistance as well as the maintenance of preclinical studies showed that curcumin inhibits DNA damage brought
the same efficacy or often a synergistic impact, accumulating the toxic about by oxidative factors such as ionizing radiation by inhibiting free
effect from each agent may lead to deleterious systemic reactions. radicals and reactive oxygen species (Shafaghati et al., 2014). NF-kB is
Therefore, the combined dietary supplements and herbal products have greatly important for the formation of nitric oxide synthase and oxida
the same effects as traditional chemotherapeutic agents with lower side tive stress, which cause cancer, so by inhibiting it, curcumin suppresses
effects (Lin et al., 2019b). The rebirth of herbal remedies is particularly the onset of cancer (Samarth et al., 2017). In oral cancer, as curcumin
significant for the treatment of cancers as more than 60 plant species are has anti-inflammatory and antioxidant qualities it prevents
now being studied as anticancer drugs (Lin et al., 2017) (Table 1). lipo-oxygenase and cyclooxygenase (COX) activities that can reduce
inflammation. COX is an important enzyme whose function is to convert
arachidonic acid to prostaglandins and thromboxanes. COX has two
Table 1
Several types of important Herbal drugs.
Drug Method Outcomes Ref/Year
Herbal Drugs
Artemisia annua In vitro • Artesunate: prevents anchorage-independent colony production, proliferation, and (Xiao et al.,
survival in the evaluated oral tongue squamous cell carcinoma (OTSCC) despite 2020)/2020
varied effectiveness.
• Indicates preferential anti-OTSCC effect via sparing healthy cells.
• Prevents mitochondrial respiration by inhibiting mitochondrial complex I and II (IV
and V are not involved), leading to oxidative stress and trauma in cell lines
characterized by low sensitivity.
Mouse xenograft model • There was no renal damage due to toxicity following dihydroartemisinin (Shi et al., 2017)/2017
intraperitoneal injection within three weeks in vivo.
• Oxidative stress was enhanced by DNA double-strand break that reduced p-STAT3
(Tyr705) nuclear localization, as well as promoted autophagic cell death (ACD) in
the Cal-27 cells. Therefore, dihydroartemisinin can provide a promising drug for
human tongue squamous cell carcinoma (TSCC).
In vitro • The Artemisinin extracts anti-inflammatory, antioxidant, and antimicrobial prop (Kim et al., 2015)/2015
erties obtained by Artemisia annua L. with four solvents were assessed indicating
Artemisinin anti-inflammatory, antioxidant, and antimicrobial effects to perio
dontopathic bacteria.
Garcinia indica In vitro • Garcinol suppressed constitutively activated STAT3 in HNSCC cells associated time- (Li et al., 2013)/2013
& and concentration-dependently that was due to the inhibition of the upstream ki
Xenograft mouse models nases (c-Src, JAK1, and JAK2) in HNSCC cell lines.
• Garcinol could downregulate different gene product expression associated with
proliferation, survival, and angiogenesis leading to a decrease in cell viability and
inducing apoptosis in HNSCC cells.
• Following an intraperitoneal injection, garcinol suppressed human HNSCC xenograft
tumors development in male athymic nu/nu mice.
• Garcinol can mediate its anti-tumor activity in HNSCC cells and mouse model by
suppressing several proinflammatory cascades.
In vitro • Based on the reports, garcinol repressed oral squamous cell carcinoma (OSCC) cell (Zhang et al.,
proliferation, cell cycle, migration and invasion, and colony production. 2019)/2019
• Treating with Garcinol reflexively enhanced glycolysis through an increase in
glycolysis and glycolytic capability.
• Based on the findings, garcinol poses opposite impacts on tumor energy metabolism
by suppressing significant inhibition of mitochondrial oxidative phosphorylation, as
well as enhancement of glycolysis in OSCC cells reflexively.
In vitro • Garcinol treatment significantly suppressed the development, proliferation, and (Aggarwal and Das,
colony generation of OSCC cells along with simultaneously induced apoptosis and 2016)/2016
cell cycle arrest.
(continued on next page)
4
Table 1 (continued )
Herbal Drugs
• No toxicity was observed in normal cells.

• Garcinol exhibits anti-proliferative, pro-apoptotic, cell-cycle regulatory, and anti-
angiogenic activities on oral cancer cells by inhibiting NF-kB and COX-2.
Tripterygium In vitro • Triptolide (TPL) is a diterpenoid triepoxide purified from a Chinese plant (Chen et al.,
wilfordii Tripterygium wilfordii Hook F and can induce apoptosis of two oral cancer cells 2009)/2009
(SCC25 and OEC-M1, as well as in KB cells) a concentration-dependently at nano
molar level.
• Based on the findings, TPL exhibits an anti-tumor activity on oral cancer and KB cells
suggesting the possible effect of TPL combined with other chemotherapeutic com
pounds or radiotherapy to treat oral cancer in the advanced stage.
In vitro and Xenografted NOD/SCID • According to findings, TPL suppressed SAS cell development after co-inoculation (Yang et al.,
mice with U937 cell lines in vitro and in vivo. 2017a)/2017
• TPL prevented the invasion, migration capacity, and angiogenesis of SAS cells after
co-inoculation with U937 cell lines.
• Co-inoculation induced the Expression levels of cytokines IL-6, IL-8, and TNF-α was,
however, TPL suppressed their expression.
• TPL inhibited the of IL-6, IL-8, and TNF-α cytokines expression, and tumor devel
opment, invasion, migration, and angiogenesis in the human tongue cancer cells co-
inoculated with macrophage-like U937 cells.
• TPL can be considered as a promising candidate among new chemotherapeutic
medications or adjuvants to modulate tumor-related macrophages in a tumor
microenvironment of HNSCC.
In vitro and patient-derived tumor • PD-L1 was overexpressed at the tumor location of oral cancer. (Kuo and Chen,
xenograft (PDTX) models • IFN drives the PD-L1 expression in oral cancer cells dose-dependently. 2019)/2019
• TPL suppresses tumor development in the oral cancer PDTX models via inhibiting the
PD-L1 expression.
• TPL also inhibits the PD-L1 expression level in the interferon-gamma
microenvironments.
In vitro • Celastrol (CEL), a pentacyclic triterpenoid, is obtained from Trypterygium wilfordii (Lin et al.,
(a Chinese herbal medicine) and has shown with several therapeutic effects on 2019a)/2019
different diseases.
• CEL caused apoptosis of HNSCC via mitochondria- and Fas-mediated pathways.
• CEL induced apoptotic cell death through the induction of cell cycle arrest at the G2/
M phase by the intrinsic and extrinsic pathways (elevated cleaved caspase-3, cas
pase-8, caspase-9, and PARP).
• Crosstalk between the two pathways was shown by an elevation in the tBid
expression.
• Cell apoptosis was moderated with CEL by down-regulating the Bcl-2expression (not
Bcl-xL). Also, JNK1/2 signaling is the principal pathway in CEL -associated
apoptosis.
• CEL can be used as an effective agent to treat multidrug-resistant oral cancer cells
(MDR)
In vitro, In vivo and In a preclinical • DcR3 overexpression has been found linked to tumor size and overall survival. (Yang et al.,
patient-derived tumor xenograft Tumor development was reduced by TPL remarkably. 2019)/2019
model • The metastasis-associated protein 1 (MTA1) expression was suppressed by TPL.
MTA1 is a transcription factor for DcR3 in vivo, in vitro, and PDTX models.
• TPL possibly exhibits its anticancer properties via suppressing DcR3 and MTA1 in
vitro, in vivo, and PDTX models.
Xenograft mouse model • TPL effectively prevented oral tumor development via the inducing cell apoptosis in (Tian et al.,
a PDTX mouse model. 2019)/2019
• In general, it can be suggested that TPL circumvented MDR of SAS/Taxol cells via
inhibiting proliferation and inducing apoptosis that was in part moderated by the
intrinsic and extrinsic apoptotic pathways, indicating a possible therapeutic effect of
TPL on Taxol-resistant human oral cancer.
Curcuma longa Golden Syrian hamsters • The following outcomes were obtained by the mucoadhesive Curcuma longa (MCL) (SCHMIDT et al.,
(Curcumin) group: a reduction significant decrease in the mucositis lesions on day 8, the greater 2020)/2020
rate of re-epithelization, and the low level of the inflammatory process, as well as a
lower level of angiogenesis and TGF-β1 epithelial labeling than the placebo and
control groups.
• MCL and chamomile showed the same effects. MCL Curcuma longa L. is effective in
promoting oral mucositis healing decreasing the inflammatory reaction and
enhancing re-epithelization.
In vitro • The research aimed at evaluating the impacts of various concentrations of four (Dehghani Nazhvani
medicinal herbs, such as saffron, ginger, cinnamon, and curcumin on the OSCC cells. et al., 2020)/2020
• They showed effectiveness in OSCC cells.
• It can be suggested that traditional medicinal plants can be promising to treat oral
cancer and provide a new window to develop new therapeutic approaches for OSCC.
In vitro and Xenograft model • Highly migratory cells indicated a reduction in the rate and directionality of (de Campos et al.,
migration after treatment with curcumin (Cur) (2 or 5 μM). 2017)/2017
• Cur in a dose-dependent fashion reduced cell-cell adhesion, particularly on tumor-
derived spheroids. Also, in a xenograft model with patient derived OSCC cell lines,
treatment with Cur reduced tumor development and aggression in comparison with
untreated tumors, suggesting the possible antitumor activity in oral cancer.
5
Herbal Drugs
• Cur in at the Lower doses can influence different steps associated with tumorigenesis,
such as migration properties; accordingly, it can be used in cancer therapy.
In vitro • Copper Supplementation caused a significant enhancement in the inhibitory activity (Lee et al., 2016)/2016
of Cur therapy on migration and viability of oral cancer cells.
• Overall, the results indicated the effect of copper to overcome the oral cancer cell’s
insensitiveness against Cur, therefore, suggest a novel approach to treat cancer.
In vitro • Cur cased a significant reduction in the proliferation and invasion of HSC-3 and SCC- (Hoornstra et al.,
25 cells. 2018)/2018
• Cur poses an anti-carcinogenic activity on the aggressiveness of OTSCC cells in vitro.
Wistar rats • In this study, the grape seed extract Burgund Mare (BM) effects on oral (Scrobota et al.,
carcinogenesis were assessed and compared with Cur 2016)/2016
• BM was found with chemopreventive effects through initiation and post-initiation of
oral carcinogenesis, decreasing local and general oxidative stress, as well as the
dysplasia intensity.
• In the post-initiation of carcinogenesis, BM and Cur were observed with the same
effects.
Resveratrol In vitro •Inhibiting proliferation dose- and time-dependently was observed in the evaluated (Yu et al., 2016)/2016
cell lines after treatment with Resveratrol.
•Resveratrol therapy caused G2/M phase cell cycle arrest and promoted the phospho-
cdc2 (Tyr 15), cyclin A2, and cyclin B1 expressions in the OSCC cells.
•It markedly increased the rate of apoptotic cells evidenced by the fluorescence-
activated cell sorting analysis.
•Therefore, Resveratrol has an inhibitory activity on the proliferation of OSCC cells
through inducing apoptosis and cell cycle arrest in the G2/M phase.
In vitro •According to the findings, Resveratrol showed a significantly lower toxic effect in (Chang et al.,
healthy oral cells and provoked ACD for forming acidic vesicular organelles and 2017)/2017
autophagic vacuoles in CAR cells with acridine orange and monodansylcadaverine
staining.
•Resveratrol also increased AMPK phosphorylation and regulates autophagy- and pro-
apoptosis-caused signals in CAR cells received resveratrol. Its provoked mRNA
expression of the autophagy gene, such as Atg5, Atg12, Beclin-1, and LC3-II in CAR
cells.
In vivo •Resveratrol decreased nuclear PD-L1 assembly increased with a STAT3 inhibitor, S31- (Ho et al., 2020)/2020
201 or Nano-diamino-tetrac (NDAT), which indicates the inactivation of STAT3 by
NDAT for inhibiting PD-L1 assembly.
•With T4, NDAT increased anti-proliferation caused by resveratrol in two cancer cell
lines.
•The results provided new information about the NDAT inhibition in thyroxine-related
pro-inflammatory activity on resveratrol-caused anticancer activities.
In vivo •T4 provoked pro-inflammatory and proliferative gene expressions as well as prolif (Chen et al.,
eration in oral cancer cells. On the contrary, resveratrol prevented these genes and 2019)/2019
stimulated anti-proliferative genes.
•T4 maintained COX-2 caused by resveratrol in the cytoplasm and inhibited COX-2
nuclear accumulation after the treatment of cancer cells with resveratrol.
•The results provided new information about the inhibitory properties of T4 on
anticancer effects caused by resveratrol by the sequential expression of PD-L1 and
inflammatory genes.
In vivo •Thyroxine inhibited the pro-apoptotic BAD expression; however, it caused prolifera (Chen et al.,
tive CCND1 expression in SSC-25 and OEC-M1 cells. 2019)/2019
•PD-L1 and BTLA expression was activated by Thyroxine in both cell lines. In contrast,
Resveratrol inhibited their expressions. On the other hand, Resveratrol stimulated BAD
expression.
•Therefore, thyroxine can induce checkpoint gene expression that possibly increases
cancer cell proliferation.
•On the other hand, Resveratrol reversed the stimulatory effects of thyroid hormone for
inducing anti-proliferation.
•The obtained results provided a novel insight into resveratrol as an antagonizer in the
thyroxine-related expression of the checkpoint and proliferative genes in oral cancers.
In vivo •Resveratrol effectively suppressed LPA-related oral cancer cell epithelial- (Kim et al., 2018)/2018
mesenchymal transition (EMT) and invasion through the downregulation of SLUG and
TWIST1 expressions.
•Thus, Resveratrol can decrease OSCC invasion and metastasis in oral cancer cases,
leading to improve survival outcomes.
In vivo •Resveratrol could activate the PPAR gamma dependent squamous differentiation gene (Diaz et al.,
Involucrin in oral cancer cells and BEAS 2B cells. 2016)/2016
•Additionally, Resveratrol significantly decreased BEAS 2B proliferation from 48 to 96
h at concentrations of 10 μM. From this data, we conclude that resveratrol can activate
PPAR gamma in vitro and resveratrol and its derivatives may also function as PPAR
gamma activators as an additional mechanism of action.
•They also conclude that inositol, eucalyptol, chalcones, and nicotinamides do not
activate PPAR gamma.
Rhodamnia Nude mice •According to findings, Oridonin suppressed proliferation and clonal production, as (Yang et al.,
rubescens well as caused G2/M cell cycle arrest and apoptosis in UM1 and SCC25 cells dose- 2018)/2018
(Oridonin) dependently.
6
Herbal Drugs
•Oridonin resulted in G2/M phase arrest in OSCC cells by down-regulation of the G2/M
transition-associated proteins, like cyclin B1 or up-regulation of cyclin D1, cyclin D3,
P21, p-CDK1, and cyclin A2.
•Also, treatment with Oridonin caused a significant inhibition of the PI3K and Akt
phosphorylation and suppressed tumor development of OSCC xenograft in nude mice.
In vitro •Oridonin (Ori) was effective to induce apoptosis through augmentation of the γH2AX (Yang et al.,
expression against DNA damage, which can be an appropriate anti-cancer medication 2017b)/2017
to treat oral cancer.
In vitro •Apoptosis of oral cancer cells is induced by Ori possibly by ROS-mediated JNK/p38 (Oh et al., 2018)/2018
MAPK as well as mitochondrial pathways; therefore, Ordn can be applicable to treat
oral cancer.
In vitro and In vivo •Ori: (Wang et al.,
xenograft mouse model •Suppressed the OSCC cell lines development in vitro and in vivo. 2017)/2017
•Reduced the proliferation and clonal generation of cultured OSCC cell lines
concentration-dependently.
•Caused arrest in the G2/M phase in OSCC cell lines, along with down-regulating
proteins associated with G2/M transition, such as cdc25C, cdc2, and cyclin B1, and the
up-regulating p53 and phosphorylated-cdc2.
•Led to OSCC cell apoptosis via activation of the intrinsic apoptotic pathway,
evidenced by an elevation in the expression of cleaved caspase 3 and caspase 9, and Bax
and caused a reduction in the expression of caspase 9 and Bcl-xl.
•Inhibited the OSCC growth in a xenograft mouse model. The immunohistochemical
assessment indicated reduced cyclin B1-positive cancer cells and increased TUNEL-
positive cancer cells in mice received Ori.
isoforms called COX-1 and COX-2. COX-1 is a constitutive isoform found 3.2. Resveratrol
in most tissues and is generally considered a housekeeping enzyme. Its
inhibition will have harmful consequences, such as a peptic ulcer or Resveratrol is a phytoalexin found in grapes and wines. By using
impaired renal blood circulation, whereas the expression of COX-2 is resveratrol, inflammatory factors, LDL cholesterol and the risk of car
limited to brain and spinal cord tissue (Bhattarai et al., 2016). The diovascular disease will reduce, which protects the body against chronic
carcinogenesis of head and neck tumors is accompanied by the over diseases by eliminating free radicals. It also protects the cells of the
expression of COX 2 (Chhaparwal et al., 2019). Curcumin inhibits the nervous system and prevents Alzheimer’s in people (Schilling, 2017).
COX-2 gene to be expressed in oral epithelial cells. COX-2 inhibitors, People with type 2 diabetes usually have insulin resistance. Resveratrol
which reduce COX-2 expression at the transcriptional level, are probably increases the sensitivity of cells to insulin and improves insulin resis
the major result of curcumin’s anti-inflammatory activity (Anuchap tance (Öztürk et al., 2017). Other benefits of this herbal medicine
reeda et al., 2019). Curcumin can preclude the activation of pathways include increasing the levels of testosterone in men, preventing the
that are linked to the NF-kB pathway, especially those linked to activator growth of viruses in the body, increasing bile secretion, and excreting
protein 1 (AP-1) and c-Jun NH2 terminal kinases (JNK) (Paunovic et al., cholesterol from the body (Kuršvietienė et al., 2016). Resveratrol can
2016; Velu et al., 2017). The AP-1 and JNK pathways form a set of regulate the signal transduction pathways that control cell growth and
terminal kinases that are take part in the cellular response to inflam division, apoptosis, inflammation, metastasis, and angiogenesis (Silva
matory cytokines, environmental stress, mitogen stimulation, and et al., 2020), as research has indicated that resveratrol causes apoptosis
apoptotic stimuli. Furthermore, curcumin downregulates a signaling in breast cancer cells (HL60 and T47D) (Wheat and Currie, 2008). The
pathway known as PI3K–AKT–mTOR by modification of the expression results of scientists’ studies of Resveratrol and its effect on oral cancer
of key genes and proteins. Thus, it can be highlighted as a promising cells showed that resveratrol increased the effect of apoptosis and
therapeutic agent to inhibit head and neck cancer growth and progres increased curcumin activity in head and neck squamous cells (HNSCC)
sion (Borges et al., 2020). However, as a disadvantage, its efficacy may lines (Yu et al., 2016). The combination of resveratrol and curcumin
be limited by poor systemic absorption when taken orally. Thus, novel induces apoptosis through enhancing PARP-1 cleavage, suppressing
delivery systems have been investigated to enhance its oral bioavail ERK1/2 phosphorylation, vacuole autophagy formation, increased LC3
ability by delivering the active components to oral tissues adjacent to the II expression and increased Bax/Bcl-2 ratio (Chen et al., 2017; El-Fattah
tumor site (Basak et al., 2020; Liu et al., 2020). et al., 2016).
The researchers also found that Resveratrol decreases cell survival
3.1.1. Tetrahydrocurcumin and enhances apoptosis in human nasopharyngeal carcinoma (NPC) by
Tetrahydrocurcumin (THC) has been known as the main curcumi activating caspase-3 as well as AMPA (Wu et al., 2018). In research done
noid metabolite of curcumin (CUR) found in turmeric. THC has been by Lin et al., the administration of different concentrations of Resvera
widely considered due to its structure stability, solubility in water trol (0-1-100 μM) induced anti-invasive activity in a human oral cancer
accessibility, and anti-oxidative effect than CUR. THC has been shown cell line (SCC-9), so this herbal medicine caused the migration of SCC-9
with anti-cancer activity by different mechanisms, such as modulating cells by preventing matrix metalloproteinase-9 (MMP-9) and 12-O-tetra
oxidative stress, inflammation, xenobiotic detoxification, metastasis, decanoyl phorbol-13-acetate (TPA) from being expressed. Resveratrol
proliferation, programmed cell death, and immunity. Although THC and was found to suppress the phosphorylation of ERK1/2 and JNK1/2, both
CUR are similar pharmacologically, the THC structure can determine its of which were involved in down-regulating protein expression and
specific and unique molecular mechanism, which makes it an appro MMP-9 transcription (Lin et al., 2015). The tripartite motif family-like 2
priate option to prevent and treat cancers (Fig. 2). Nonetheless, THC (TRIML2) overexpression can cause tumor development at the G1 phase
should be assessed more because only a few pharmacokinetic and oral found in cell cycle assessment that leads to inadequate control via
bioavailability investigations have been conducted (Lai et al., 2020). down-regulating p21Cip1 expression. Resveratrol up-regulates the
p21Cip1 by the TRIML2 expression. Thus, the TRIML2 expression status
7
may be regarded as an index for OSCC progression and as a promising IHGK cells through the apoptosis process (Yamachika et al., 2004).
novel agent for oral cancer treatment by TRIML2 (Silva et al., 2020). In The way apoptosis induction by artemisinin and its derivatives
terms of safety, some animal studies showed that oral administration of operates has not been precisely elucidated (Zhu et al., 2020), but there is
Resveratrol at high doses can contribute to renal toxicity (Crowell et al., a hypothesis that artemisinin and its derivatives activate caspase-3,
2004). However, experiments performed in humans reported that this which leads to apoptosis (Yamachika et al., 2004). In another similar
compound has low toxicity since it was well tolerated in the short-term study to investigate the antitumor activity of artemisinin, there was a
(Almeida et al., 2009). It has been reported that administration of 1000 comparison between the influence of the different derivatives of arte
or 300 mg resveratrol per kilogram body weight per day did not result in misinin on the YD-10B cell line, which is a human oral squamous cell
nephrotoxic findings (Crowell et al., 2004). carcinoma cell line, with that of chemotherapy drugs such as paclitaxel
(Taxol), 5-fluorouracil (5-FU), and cisplatin. The findings of this
3.3. Artemisia annua research showed that deoxy artemisinin trimer has a stronger antitumor
effect on tumor cells than the other conventional chemotherapy drugs
Artemisia annua is a short-lived daily plant from the Asteraceae studied. Also, as artemisinin and its derivatives can cause apoptosis, it is
family, which has nearly 400 species worldwide and has a stiff brown confirmed that they have the potential to act as chemotherapeutic
stem. Research has been conducted on Artesunate and it has been agents since many anticancer drugs induce apoptosis in tumor cells to
considered a powerful anti-cancer compound (Efferth, 2005). In one achieve their antitumor effects. The safety of artemisinin, however,
study, the effect of the artesunate on 55 different cancer cell lines, tolerance has been reported, studies have not indicated any
including leukemia, melanoma, lung cancer, colorectal cancer, renal cross-resistance to other drugs or serious harmful consequences after
cancer, ovarian cancer, and central nervous system tumors was exam administration to humans (Das, 2015; Gruber et al., 2018; Yamachika
ined (Efferth, 2005). The researchers stated that artemisia had the et al., 2004; Zhang et al., 2018). The dose-dependent toxic effect has
greatest effect on leukemia and colon cancer. Results showed that this been the main issue of anticancer treatment, which could be overcome
plant has antioxidant and anticancer characteristics because of phenolic through an increase in its effectiveness with lower toxic drug levels.
compounds as well as anonymous compounds within Artemisia annua Although artemisinin derivatives are widely used, it has toxic effects on
(Efferth, 2005; Khan et al., 2020). Recently, derivative forms of mono human. The toxic effects of artemisinin-like products have appeared
mers, dimers, and artemisinin trimers are synthesized from deoxy after a long-term application, however, therapies up to a year have no
artemisinin. It has been suggested that the antitumor activity of dimers complications (Berger et al., 2005). Dihydroartemisinin is one of the
and trimers is much stronger than monomers (Nam et al., 2007). Arte derivatives of artemisinin with high neurotoxic effects that acts dose-
misinin and its derivatives have antiproliferative and antiseptic effects and time-dependently (≥7 days) (Si et al., 2007). Therefore, a quick
(Efferth, 2005). Furthermore, they also cause apoptosis in tumor cells decrease of artemisinin in oral type is more immune compared with
because they damage the target proteins, which leads to lipid peroxi slow-release/oil-based intramuscular formulations (Gordi and Lepist,
dation using carbon-centered radicals or reactive oxygen species 2004). Clinical doses for malaria has been shown three times more
(Yamachika et al., 2004). In a study aimed at investigating the effects of compared with its anticancer effect (Efferth et al., 2003). Therefore,
artemisinin on oral cancer, different artemisinin derivatives were stud artemisinin can be used as an anticancer drug because it is applicable in
ied to evaluate the strong antitumor influence of 5-Fluorouracil combination with no higher rate of adverse effects while effectiveness
compared to a conventional chemotherapy regimen on HPV 16 human and dose-reduction of more anticancer drugs with toxic effects is
gingival epithelial cells (IHGK). The results showed that 82% of cells possible. Animal research has revealed brainstem neurotoxic encepha
treated with artemisinin and 18% of cells treated with 5-FU had positive lopathy commonly correlated with long-term high-dose therapies (Si
results. The results have shown that Dihydroartemisinin (DAR) can kill et al., 2007).
Fig. 2. Mechanisms are used by multi-step tumorigenesis as well as the mechanism of the anticancer effect of tetrahydrocurcumin. MET: mesenchymal-epithelial
transition; ROS: reactive oxygen species. Reprinted with permission from ref (Lai et al., 2020) with permission from MDPI.
8
3.4. Garcinia indica substance (Dariya et al., 2019).
Garcinol is a polyisopronylated benzophenone from the bark of the 3.5. Rabdosiae rubescens
Garcinia indica tree, commonly known as kokum. This plant is widely
found in tropical regions (Yamachika et al., 2004). Several recent studies Rabdosiae rubescens is a Chinese medicinal plant from the Lam
have demonstrated the antitumor potential of garcinol against various iaceae family. This medicinal plant has several biological activities such
cancers including breast cancer, colon cancer, pancreas cancer, and as antioxidant, antibacterial, anti-inflammatory, anti-parasitic and anti-
leukemia in not only in vitro studies but also in vivo studies (Schobert apoptotic, anti-cancer, and neurotoxic effects (Wen et al., 2019). R.
and Biersack, 2019). The garcinol of G. indica has had positive thera rubescens contain important chemical compounds including mono
peutic effects on HT-29 and HCT116 colon cancer cell lines (Hong et al., terpenes, sesquiterpene, diterpene, and terpenoids. Oridonin (Ordn) is a
2007). In a study by Pan et al., They stated that G. indica fruit extracts tetracyclic terpenoid, which is the most important active compound in
are highly effective in activating caspase-3/CPP32 and the breakdown R. rubescens. Oridonin has been considered for its high potential to
poly (ADP - ribose) polymerase (PARP) protein to inhibit human leu inhibit the growth and causing apoptosis in cancer cells such as hepa
kemia in the HL-60 cell line (Pan et al., 2001). In his study, Aggarwal tocellular carcinoma, breast, stomach, skin, colorectal, gall bladder, and
showed that garcinol is capable of growth and proliferation-dependent pancreatic cancers (Zhang et al., 2017). Furthermore, for a long time, R.
inhibition in SCC-4, SCC-9, and SCC-25 oral cancer cell lines (Aggar rubescens has been in use in China because it is not very toxic and it does
wal and Das, 2016). According to recent studies, garcinol is capable of not have side-effect (Aggarwal and Das, 2016). In a study investigating
strengthening the influence of cisplatin by negatively regulating various the anticancer effects of Oridonin on HN22 and HSC4 oral cancer cells, it
inflammatory and proliferative markers in HNSCC (Zhang et al., 2019). was observed that depending on the dose administered, and this herbal
Research has shown that garcinol exerts its antitumor function by dis drug greatly decreased cell proliferation and colony-forming in both
rupting cell cycle progression (Khan et al., 2020). Cell cycle machinery HN22 and HSC4 cells (Oh et al., 2018). The results of this study suggest
has often been shown to change during cancer. The major role of these that oridonin is a direct cause of cell apoptosis through ROS production
mechanisms is cyclin-dependent kinases (cdks), which contain the and MAPK signaling pathways. It seems that Ordn can be relied upon as
starting, progressing, and complementary events of the cell cycle. a drug candidate that can be used for the inhibition of the growth of oral
Different tumor cells seem to be possibly influenced by garcinol cancer cells (Oh et al., 2018).
regardless of the stage of the cell cycle they are in (Aggarwal and Das,
2016). What is important is that garcinol does not cause pathological 3.6. Tripterygium wilfordii
changes in the liver and other organs, including the kidneys, lungs,
heart, and esophagus, indicating the low toxicity of garcinol (Aggarwal Tripterygium wilfordii from the family Celastraceae is a native plant
and Das, 2016; Schobert and Biersack, 2019). Therefore, it seems that of Korea, China, and Japan. It is popular as a treatment for a variety of
this medicinal plant has the characteristics of an ideal anticancer diseases, such as rheumatoid arthritis, systemic lupus erythematosus,
Fig. 3. Triptolide (TPL) had an inhibitory effect on tumor growth in DcR3-overexpressing oral cancer patient-derived tumor xenograft (PDTX) models. (A) Alter
ations of the volume of tumor in 134-PDTX models (n = 4) after the administration of TPL (0.15 mg/kg daily intraperitoneally) and phosphate-buffered saline (PBS)
(vehicle control; n = 4) over 28 days. Vernier calipers were used to assess the diameter of the tumor two times a day over 28 days; the volume of the tumor was
measured against those of controls. P < 0.05 was deemed statistically significant. (B) When the mice sacrificed the weight of the tumor was measured. (C) The
bodyweight of the mice did not show a noticeable change in comparison with that of the vehicle controls. (D) When TPL or PBS (vehicle control) was administered,
the researcher proceeded with Hematoxylin, eosin staining, and immunohistochemistry. The 134-PDTX model stained positive for DcR3. The result of staining was
positive for DcR3 in the case of the 134-PDTX model. (E) The result of staining was positive for DcR3 in the case of the SAS xenograft model. In the staining process,
immunodetectable proteins were stained brown; nuclei were counterstained blue. Original magnification: × 400. Reprinted with permission from ref (Yang et al.,
2019) with permission from Wiley.
9
nephritis, and asthma, and enhances the anti-tumor effect in various research has indicated that EGFR monoclonal antibodies in this disease
cancer cells. This medicinal plant produces the important bioactive are active against small tyrosine kinase inhibitors. The activation of the
compound triptolide (Khan et al., 2020). Triptolide (TPL), a diterpenoid EGFR oncogene protein occurs early on in head and neck cancer
triepoxide derived from Tripterygium wilfordii, has potent anti-cancer (Galstyan et al., 2020; Kono et al., 2012).
properties and is considered an immunosuppressive and
anti-proliferative agent (Brinker et al., 2007). The influence of this 4.1. Cetuximab
medicinal plant on oral cancer was first investigated in 2009 by Wu
Chen et al. The results of their study showed that TPL induced cell death Cetuximab can be administered together with radiation therapy to
at nanomolar concentration and thus was able to stop oral cancer and treat cancers in the first phase. For more advanced cancers, it may be
reduce KB cell growth and lead to cell apoptosis. The induction of combined with standard chemotherapy drugs such as cisplatin, or it may
apoptosis in oral cancer and KB cells was supported by caspase activa be used alone (Bauml et al., 2017). Combining radiotherapy with
tion mediated by TPL. They also emphasized that TPL destroys oral cetuximab, as an EGFR-aimed complementary treatment, enhances the
cancer cells through a p53-independent pathway (Chen et al., 2009). In positive influence of radiation and reduce its toxicity. It has been
an experiment, Yang et al. (2019) observed that TPL greatly reduced the demonstrated that radiation therapy increases EGFR expression in can
growth of tumors from the 134-PDTX model (extracted from oral cancer cer cells, which enhances the effects of radiation (Higgins et al., 2016).
patients), while the vehicle (PBS) controls did not show such an effect Research has shown that cetuximab is widely used in colorectal and lung
(Figs. 3A and 4B). During the experiment, TPL proved to be non-toxic cancers in addition to being recognized as a treatment for oral cancer
and did not lead to weight loss in patients (Fig. 3C). According to (Kono et al., 2012).
their observations, the expression of DcR3 in mice with clinical tumor
tissue was lessened following the administration of TPL (Fig. 3D). Also,
4.2. Zalutumumab (HuMax-EGFR)
the expression of DcR3 proved to be much lower in subjects treated with
TPL in the 134-PDTX and SAS xenograft models (Fig. 3E).
Zalutumumab is a human IgG1k moAb that targets EGFR. Results of
clinical trials have shown that zalutumumab possesses a ligand-binding
4. Bio-drugs
inhibitory property through competition between EGF and TGF-α to
EGFR. Following that, this action disrupts receptor binding and dimer
Cancer research has always been looking for new therapeutic options
formation and inhibits EGFR activity also in addition to promoting
that can minimize the impact on natural cells while simultaneously
anticancer activity by antibody-dependent cellular cytotoxicity (ADCC)
killing the cancer cells effectively. New science has emerged as bio
(Liu et al., 2017; Zibelman and Mehra, 2016). Zalutumumab has also
therapy. Biological treatment involves the use of agents derived from
been studied as a treatment in cancers such as breast and colorectal
living organisms or compounds produced in vitro to treat diseases. For
cancers but has been used specifically in cancers of the head, neck, and
example, the biological treatment of psoriasis or the biological treat
mouth, which have been the focus of much research (Kono et al., 2012).
ment of rheumatism and the biological treatment of cancer (Tricoli
In one trial study, 28 incurable oral cancer patients were treated with
et al., 2016). Biological therapy can be used as a specific treatment for
zalutumumab (Zibelman and Mehra, 2016). Other similar studies have
cancer, or to reduce some of the side effects of cancer treatment, such as
also seen remarkable results in the treatment of patients with incurable
the side effects of chemotherapy (Schirrmacher, 2019). Some biological
HNSCC (Machiels et al., 2011).
treatments for cancer include the use of vaccines or bacteria to stimulate
the immune system to work against cancer cells (Carter et al., 2016).
These types of biological treatment often called immunotherapy or 4.3. Panitumumab (ABX-EGF)
biological response modification therapies, do not directly target cancer
cells. The other most important and challenging biological treatment is Panitumumab is a fully human IgG2 moAb that blocks EGFR, on
the use of monoclonal antibodies (moAbs) that directly target cancer which a lot of research has been done, proving it to be very useful in
cells (Lambert and Berkenblit, 2018). Because of the great importance of treating metastatic colorectal cancer and non-small cell lung cancers
monoclonal antibodies, their use and impact on head and neck and oral (Gao et al., 2018). Having an IgG2 antibody, rather than IgG1, may
cancers are being discussed (SHRUTHI and SINGH, 2010) (Table 2). The cause the onset of antitumor activity by activating ADCC and NK cells
expression of more than 90% of epidermal growth factor receptor (Rösner et al., 2019; Sasada et al., 2016). Results from clinical trials have
(EGFR) proteins in the oral cavity and oral and pharyngeal cancer cells shown that panitumumab has a high affinity for EGFR, which is ach
has made EGFR a reasonable therapeutic target, so a large body of ieved by blocking the binding of TGF-α and EGF to EGFR and preventing
the release of relevant signals (Foon et al., 2004). In a study of mice with
Fig. 4. (A) CT before treatment: a stable

disease with no indications of metastases.
Surgical resection was not possible for
removing the tumor. (B) Eight weeks after
treatment with nivolumab and ipilimumab,
CT showed that the tumor had become
significantly smaller. (C) Four months after
the onset of treatment, MRI indicated that
remission was nearly complete. Tumor
manifestations are illustrated by arrows.
Reprinted with permission from ref (Schwab
et al., 2018) with permission from Karger.
10
Table 2
Several types of important Bio-drugs.
Bio-drugs
Cetuximab Human in •Cetuximab can be a therapeutic candidate in cases with unresectable locally advanced (LA) and (Naruse et al., 2016)/2016
vivo recurrentmetastatic
̸ (R̸M) OSCC, and cases with distant metastases (DMs).
In vitro •Epidermal growth factor (EGF) priming of OSCC enhanced such EMT-initiating effect of the extracellular vesicles (Fujiwara et al.,
(Basak et al.) obtained from OSCC. 2018a)/2018
•Cetuximab highly blocked the internalization and pro-EMT impacts of the OSCC-EVs.
•Therefore, OSCC-derived EVs change healthy epithelial cells to a mesenchymal phenotype, and cetuximab, an
anti- EGF Receptor (EGFR) therapeutic antibody, can inhibit this carcinogenic activity of the OSCC-EVs.
In vitro •Cetuximab activated the p38 MAPK pathways in human skin cells (human keratinocytes [HaCaT]) and inhibited (Uzawa et al., 2019)/2019
c-Fos-associated signals in human embryonic kidney cells (HEK293).
•SB203580, p38 inhibitor, suppressed the p38 MAPK expression in HaCaT cells and flavagline reactivated c-Fos-
associated factors in HEK293 cells.
•The two compounds did not interfere with the cetuximab effect and flavagline caused an additive inhibitory
impact on OSCC growth in vivo.
•Cetuximab combined with such drugs for cetuximab-related toxicities can be regarded as a proper treatment
approach for cases with OSCC.
In vitro •Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) to oral cancer cells was found at 0.1 (Nakamura et al.,
μg/ml concentration. 2019)/2019
•ADCC and EGFR molecules counts on the surface of oral cancer cells were highly correlated.
•The proposed working mechanism of cetuximab is thought to include, and EGFR expression in tumor cells can be a
predictive marker for evaluating the effectiveness of treatment with cetuximab.
In vitro •Cetuximab enhanced the EGFR-EVs secretion through OSCC cells and could not suppress EGF-driven EGFR-EVs (Fujiwara et al.,
secretion. 2018b)/2018
•Cetuximab was strongly released with the EGFR-EVs via the OSCC cells.
•Therefore, EGF promoted the level of mesenchymal characteristics in OSCC cells as well as EGFR-EVs release that
involve cetuximab resistance.
Mouse •Tumor cells collected from the recurrent cetuximab-resistant xenograft models were found with lower EGFR (Yin et al., 2018)/2018
orthotopic expression; however, they showed remarkably higher p-Smad1/5/8 levels.
xenograft •After receiving bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 caused a significant
reduction in cetuximab-resistant OSCC tumor development, and combination therapy with DMH1 and cetuximab
significantly decreased relapsed tumor development in vivo.
•Also, the p-Smad1/5/8 level increased in cetuximab-resistant cases, which was associated with a weak prognosis.
•In summary, BMP7-p-Smad1/5/8 signaling is crucial for acquiring cetuximab resistance, and cetuximab and a
BMP signaling inhibitor can be used as a novel therapeutic approach to overcome acquired resistance to cetuximab
in OSCC.
Nivolumab Markov •Nivolumab is superior to cetuximab monotherapy; however, it needs a willingness-to-pay a minimum of (Ward et al., 2017)/2017
simulation $150,000/QALY to be regarded as cost-effective than DTX or MTX.
model •Selecting by PD-L1 did not significantly improve the nivolumab cost-effectiveness.
•This can inform the patient selection and clinical care pathways development.
Clinical •Nivolumab caused a significant improvement in OS at the primary assessment and resulted in longer OS benefit (Ferris et al., 2018)/2018
versus investigator’s choice (IC) and maintenance of a manageable and consistent safety profile with a follow-up of
2 years.
•Nivolumab resulted in OS benefit regardless of PD-L1 expression and HPV status.
Clinical Case •In this case report, a case with successful treatment with nivolumab combined with ipilimumab was reported for (Schwab et al., 2018)/2018
Report the first time to treat refractory metastatic HNSCC.
•Complete remission was obtained four months following treatment and moderate and reversible complications
were observed.
•Therefore, the combined nivolumab and ipilimumab is a promising candidate to treat metastatic SCCHN.
Phase III •In cases with platinum-refractory, recurrent SCCHN, those treated with nivolumab showed longer OS compared (Ferris et al., 2016)/2016
clinical trial with cases treated with standard, monotherapy.
Phase III •Nivolumab postponed time to deterioration of quality of life (QoL) as a patient-reported outcome in comparison (Harrington et al.,
clinical trial with monotherapy of IC in cases with platinum-refractory recurrent or metastatic (R/M) SCCHN. 2017)/2017
•Considering the urgent need in these cases, as well as and the significance of maintaining or increasing QoL in
cases with R/M SCCHN, the results suggest nivolumab as a novel standard-of-care candidate in this setting.
Phase III •Data indicate a small subgroup of patients, but based on the findings, nivolumab is suggested as first-line therapy (Gillison et al., 2018)/2018
clinical trial in cases with R/M HNSCC who progressed through six months of platinum-oriented therapy in the adjuvant or
primary setting.
Phase III •Nivolumab was found effective compared with IC irrespective of prior cetuximab consumption, indicating its use (Ferris et al., 2019)/2019
clinical trial in cases with R/M HNSCC with/without prior cetuximab use.
•The reduced risk of death following nivolumab in comparison with IC was greater among cases without prior
cetuximab use compared with prior cetuximab use.
Zalutumumab Phase III •Zalutumumab was found with acceptable toxic effects in cases with head and neck cancer. Rash was the (Schick et al., 2012)/2012
clinical trial commonest side effect.
•Because of the toxic effect, zalutumumab has become an appealing candidate for cases who have pretreated and/
or cases with poor performance status because of concurrent co-morbidities. Because the molecule is completely
human, hypersensitivity against the drug is less likely to occur.
•Zalutumumab can be useful at low doses via antibody-dependent cellular cytotoxicity.
•Based on the results of Phase I and II clinical trials, zalutumumab can be suggested as a useful agent to treat locally
advanced head and neck cancer. The Phase III randomized trial results also indicated promising survival rates
compared with the best supportive care.
•The findings of other ongoing Phase III clinical trials may present more information on zalutumumab to be used as
a drug.
Phase II •Zalutumumab was found effective in platinum-refractory platinum-refractory R/M HNSCC cases, and dose (Saloura et al., 2014)/2014
clinical trial titration was possible according to skin rash assessment.
11
Bio-drugs
Phase III •OS showed no increase with zalutumumab, but progression-free survival showed an increase in cases with (Machiels et al.,
clinical trial recurrent HNSCC who did not respond to platinum-based chemotherapy. 2011)/2011
•Dose titration of Zalutumumab based on skin rash is safe.
Phase II •19% of the cases showed Zalutumumab-associated Grade 3–4 AEs and were skin rash, hypomagnesemia, and (Saloura et al., 2014)/2014
clinical trial pneumonitis.
•Infusion-induced reactions were observed in 33% of cases.
•The rate of all-cause grade 3-4 adverse events (AEs) was 62%, including infections, gastrointestinal disorders,
hypokalemia, dyspnea, and anemia. Zalutumumab was effective in platinum-refractory R/M HNSCC cases and
dosing titration based on skin rash assessment was possible.
Panitumumab Phase I •Two-phase I trials were for anti- EGFR antibodies cetuximab and panitumumab. (Gao et al., 2018)/2018
clinical trials •Panitumumab and cetuximab pose toxic effects and pharmacodynamic properties matching the parent compound,
therefore, other therapeutic antibodies can be repurposed as imaging drugs as they have limited preclinical
toxicology data.
Phase II •The combined Panitumumab and PTX provide encouraging outcomes with preserved QoL as well as a desirable (del Barco Morillo et al.,
clinical trial safety profile. 2016)/2016
Phase II •The overall response rate of 4%, the disease management rate of 39%, Median progression-free survival of 1.4 (Rischin et al., 2016)/2016
clinical trial months, and Median OS of 5.1 months were obtained.
•The commonest AEs included rash/dermatitis acneiform, fatigue, dry skin, and hypomagnesemia.
•Panitumumab single-agent therapy showed limited activity in cases treated with R/M HNSCC.
In vitro •The tumor cells showed a limited overall response to chemotherapy drugs. (Hartmann et al.,
•Five cell lines of HNSCC were applied in this research, of which only one cell line indicated a cytostatic effect 2013)/2013
following treatment using cetuximab and panitumumab.
•The results showed a relationship between the effectiveness of EGFR inhibitors and different MAGE-A subgroups
to treat HNSCC.
In vitro •The four HNSCC lines showed a poor response to cetuximab and panitumumab. (Hartmann et al.,
•Lower EGFR expression resulted in more effective anti-EGFR treatment in head and neck cancer cell lines. 2014)/2014
•Based on the results, the selection of patients for receiving cetuximab and panitumumab treatment for HNSCC
should be considered.
Fluorescence •Panitumumab-IRDye800 can be used in a clinical setting to detect and remove microscopic HNSCC by available (Heath et al., 2012)/2012
imaging intraoperative optical imaging hardware and can promote the evaluation of frozen and permanent pathology.
hardware
Phase II •In cases with locally advanced HNSCC, adding panitumumab to standard fractionation radiotherapy and cisplatin (Mesía et al., 2015)/2015
clinical trial showed no favorable outcome, and the EGFR inhibition effect in such cases should be reassessed.
Nimotuzumab Phase II •Regarding resectable HNSCC, the nimotuzumab and PF regimen (fluorouracil), as induction treatment, was found (Zhao et al., 2012)/2012
clinical trial useful to preserve the organ function and the toxic effects were well tolerated.
Clinical trial •Treatment was immune and grade I or II asthenia, fever, headache, and chills were the commonest AEs. (Rodríguez et al.,
•The skin rash was not reported. 2010)/2010
•The complete response rate improved in cases received nimotuzumab than the placebo.
•Nimotuzumab-treated cases showed improved survival.
•Following the Harrington-Fleming test, the survival benefit was more significant, as a weighted log-rank test that
distinguishes patients with different survival time.
•Also, a preliminary biomarker analysis reported a remarkable survival improvement for nimotuzumab-received
cases than the controls for cases with EGFR positive tumors.
•All cases had improved QoL and general and specific symptoms of the disease were reduced.
Clinical trial •The combination of nimotuzumab and induction chemotherapy and chemoradiation is an alternative to (Subramanium et al.,
concurrent chemoradiotherapy in HNSCC because of the overexpression of EGFR receptors. 2015)/2015
•More studies (using a larger study setting) are needed to evaluate the findings.
•Survival rate significantly improved in nimotuzumab-received patients than controls for cases with EGFR positive
tumors.
•All cases had improved QoL and general and specific symptoms of the disease were reduced.
Clinical Trial •Anti-EGFR monoclonal antibody (nimotuzumab) is immune and effective according to the loco-regional response (Somani et al., 2013)/2013
and supports the phase II results.
•The increased long-term survival according to this promising response rate should be more analyzed, particularly
in cases that developed inoperable locally advanced HNSCC.
Clinical Trial •Adding nimotuzumab to standard treatment resulted in encouraging response rate and survival outcomes in R/M (Subramanian et al.,
HNSCC cases with no additional toxic effects. 2018)/2018
In vitro •Nimotuzumab could kill EGFR + tumor cells through natural killer (NK) cell mediated ADCC. (Mazorra et al.,
•Nimotuzumab-activated NK cells improved dendritic cell (DC) maturation as well as EGFR-specific CD8+ T cell 2017)/2017
priming. Nimotuzumab up-regulated some immune checkpoint molecules on NK cells (TIM-3) and DC (PD-L1) less
than another EGFR mAb, cetuximab.
•Also, nimotuzumab-treated HNSCC cases were found with circulating EGFR-specific T cells.
•Also, the combination of nimotuzumab and cisplatin-based chemotherapy and radiation enhanced the rate of
peripheral CD4+CD39+FOXP3+Tregs that were reduced to baseline levels following using nimotuzumab as
monotherapy.
•The circulating NK cells rate was stable through the therapy.
•Nimotuzumab-caused, NK cell-mediated DC priming induced anti-EGFR specific T cells in HNSCC cases.
•More studies are needed to assess the relationship between EGFR-specific T cells and the outcome of nimotuzumab
treatment.
Human in •The combined chemoradiation therapy and Nimotuzumab were well tolerable. (Sundaram et al.,
vivo •Adding Nimotuzumab to concurrent chemoradiation therapy regimen showed no toxic effect. 2014)/2014
•Combined Nimotuzumab and concurrent chemotherapy and radiation was safe and effective considering the
locoregional response and supports the phase 2 data in HNSCC cases. The improved survival rate should be more
evaluated in a larger study setting.
12
oral cancer, it was discovered that panitumumab could inhibit tumor on healthy cells (Larsen et al., 2000).
growth better than EGFR alone or radiation therapy (Kruser et al., In this regard, various strategies for cancer therapy have been
2007). evolved by putting nanoparticles as their base, including magnetic
therapy, photodynamic therapy (PDT), photothermal therapy (PTT),
4.4. Nivolumab radiotherapy, and ultrasound. Despite the effectiveness of nanoparticle-
oriented cancer therapies, a promising synergistic effect by a combina
Nivolumab, also known as BMS-936558 or MDX1106, is a pro tion of two or more treatment techniques has been regarded. Signifi
grammed death 1 (PD-1) inhibitor antibody. It is administered intrave cantly enhanced anti-tumor efficacy has been achieved by combined
nously, which has been confirmed for recurrent or metastatic head and treatment strategies, such as PTT and PDT combined therapy, Chemo
neck cancer (R/M HNC) (Ferris et al., 2019). It is currently being used to therapy and PTT combined therapy, Chemo-photodynamic combined
treat many advanced cancers, including melanoma, non-small cell lung therapy, Immunotherapy and photothermal combined therapy (Xin
cancer, bladder cancer, kidney cancer, colorectal cancer, classic Hodg et al., 2017).
kin’s lymphoma, and endothelial cancer, which interferes with the
growth and spread of cancer cells in the body (Schwab et al., 2018). 5.2. Cisplatin (DDP)
Nivolumab is a fully human IgG4 monoclonal antibody that binds to the
PD-1 receptor and inhibits the interaction between the receptor and its Cisplatin is one of the golden ways in chemotherapy that has been
ligands PD-L1 and PD-L2. However, Survival Benefits were observed in around for over 30 years. Together with other analogues such as car
patients, regardless of the amount of PD-1 in their tumors. Because boplatin, oxaliplatin, and satraplatin, it is useful in the treatment of
PD-L1 tumors have shown the best response to nivolumab, it is impor malignancies including lung, breast, germ cell, and head and neck
tant to consider the proportions of head and neck squamous cell carci cancers as well as gynecological, testicular, and ovarian cancers (Rabik
nomas that represent this ligand (Ferris et al., 2018; Ward et al., 2017). and Dolan, 2007). Cisplatin is the oldest member of this family with
Schwab et al. (2018) did a study in which the PD-1 inhibitor nivolumab known toxicity characteristics including emesis, renal dysfunction,
and the anti-CTLA4 antibody ipilimumab were used. The 46-year-old neurotoxicity, ototoxicity, and cytotoxicity (Ketabat et al., 2019).
male patient, who was suffering from refractory squamous cell head Cisplatin, with its platinum agent, disrupts the function of cellular DNA,
and neck cancer, recovered completely after 4 months, and only suffered leading to apoptosis. It also utilizes other intracellular components, such
mild and reversible side effects (Fig. 4). as proteins, lipids, RNA, and mitochondrial RNA, leading to the for
mation of covalent DNA compounds and performing its function (Dasari
5. Synthetic drugs and Tchounwou, 2014). During one study, the results of the concomitant
use of high-dose Cisplatin with radiation therapy for head and neck
Synthetic drugs, as chemically developed anticancer agents, are used squamous cell carcinoma showed that subjects under study had a 40%
on their own or combined to treat oral cancer, the most important of positive response to treatment over 19 months (Adelstein et al., 2003;
which are Cisplatin, Docetaxel, Doxorubicin, 5-FU, Paclitaxel, and Bernier et al., 2005). In another study about the role of DDP in radio
Methotrexate (Table 3). therapy, it was found that the overall survival (OS) rate of patients with
oral cancer increased dramatically with the addition of DDP compared
5.1. Drug delivery to the group treated only with radiation (Bernier et al., 2005).
Despite the many benefits of Cisplatin, unfortunately, it can lead to
Patients tend to prefer orally administered anticancer drugs because severe kidney complications and even kidney failure. One method that is
they make outpatient treatment possible and are more convenient. Oral under investigation in this field is the use of porous Fe3O4 nanoparticles
medications also prevent the patient’s body from being exposed to as DDP carriers and their delivery to various sites (Ketabat et al., 2019).
toxins for a long time (Calixto et al., 2014). On the other hand, The main advantage of these nanoparticles can be their protection of
chemotherapy has limitations such as low solubility in aqueous liquids, DDP against plasma proteins and biomolecules and their prevention of
low permeability, and poor bioavailability (Al-Heibshy et al., 2019). On inactivation until they reach the target site. Another advantage of using
the flip side, one of the most direct methods of drug absorption is nanoparticles is their ability to control the DDP release rate by changing
intravenous injection. If the intravenous injection is used, the drug the nanoparticle pore size and pH (Cheng et al., 2009; Ketabat et al.,
immediately becomes fully bioavailable. Therefore, this pathway, while 2019). Another way to reduce the side effects of Cisplatin is by using
having more impact, can be dangerous because as a result of delivering Carboplatin, a DDP analog. However, according to a recent study
high concentrations of drugs to normal tissues, healthy tissues may be comparing DDP and carboplatin, DDP has a significant advantage over
damaged more and there might be more side effects (Calixto et al., carboplatin in the chemotherapy results of oral cancer (Ho et al., 2016;
2014). There are fewer side effects, carrier-based drug delivery systems Ketabat et al., 2019).
such as the administration of chemotherapeutics via intra-tumoral in
jection, local delivery, photo-thermal administration using carrier-based 5.3. Docetaxel (DTX)
drug delivery systems, and ultra-sonoporation using microbubbles to
keep the release of drugs under control (Fig. 5.І), are adopted instead of Docetaxel is extracted from the bark extract of Taxus brevifolia, a
using chemotherapeutic agents on their own (Ketabat et al., 2019). tree of the diterpenoid family and it is an effective anti-cancer drug that
Fig. 5.ІІ illustrates the various carrier systems according to nano has significant antitumor activity (Cohen et al., 2019) against many
particles, nanolipids, and hydrogels (Ketabat et al., 2019). human neoplasms, including those resistant to doxorubicin, cisplatin,
and vincristine (Hiew et al., 2019). This drug acts through the stabili
5.1.1. Nanoparticles zation of tubulin and the inhibition of the cell cycle in the G2M phase
Developing cancer nanotherapeutics has been recently widely (Zhu et al., 2010). In a clinical trial, the efficacy of DTX in SCCHN cancer
considered. They overcome many restrictions of common therapies, like was investigated. Of the patients studied, 9% had a complete response to
nonspecific biodistribution, limited water solubility, and poor treatment and 31% had a lesser response to the drug (Colevas and
bioavailability. Nanoparticles characterized by tuned size and surface Posner, 1998). Docetaxel has low oral bioavailability and is not rec
features are the main parts of nanotherapeutics and developed for ommended for oral administration. Since due to its high hydrophobicity,
delivering anti-cancer agents to tumor cells (Xin et al., 2017). Through this drug is administered intravenously in most cancer patients (Sohail
passive or active targeting approaches, nanoparticles enhance the et al., 2018). Docetaxel is metabolized in the body by the liver and then
intracellular level of medicines in cancer cells and prevent toxic effects excreted in the stool. Therefore, caution and dose reduction should be
13
Table 3
Several types of important Synthetic drugs.
Synthetic Drugs
Cisplatin In vitro •YC-1 (Lee et al., 2017)/2017

•Caused reduction viability of CAR cells dose- and time-dependently revealed by MTT approach.
•Suppressed cell proliferation and decreased cell confluence time-dependently. YC-1 enhanced G0/G1 phase arrest
and stimulated apoptosis in CAR cells.
•Enhanced the caspase-9 and caspase-3activities, interrupted the mitochondrial membrane potential (AYm), and
provoked ROS generation in CAR cells.
•Induced DNA fragmentation, a late event in apoptosis.
•In summary, YC-1 inhibited the viability of cisplatin-resistant CAR cells by preventing cell proliferation, G0/G1
phase cell cycle arrest, and activating mitochondria-associated apoptosis.
Human in •Performing Concurrent Chemoradiotherapy (CCRT) by intravenous administration of cisplatin and docetaxel (DTX) (Sato et al., 2019)/2019
vivo in cases with advanced oral cancer.
•The outcomes were comparable to the results of standard CCRT regarding advanced HNSCC through intravenous
injection, and fewer cases of toxicity were reported.
•CCRT is immune and effective for advanced oral cancer.
Human in •Regarding induction chemotherapy, adding taxane (DTX/paclitaxel (PTX)) to cisplatin and fluorouracil (TPF (Chiang et al., 2018)/2018
vivo regimen) has been reported that has been more effective compared with the common cisplatin and fluorouracil (PF
regimen).
•Considering the regimen for induction chemotherapy, two classic trials revealed that TPF induction is more
effective than PF. It then was approved by the FDA (DTX for induction chemotherapy), however, comparing the
currently available standards of care was not addressed.
•Based on the results of two large scale investigations, TPF therapy led to a median OS of 4 months, and the TPF
group was found with favorable outcomes and preservation of the larynx.
In vitro •The research aimed at synthesizing novel polymeric nanoparticles (NPs) bound with cisplatin to treat oral cancer. (Pornpitchanarong et al.,
The cisplatin-loaded NPs showed a higher rate in the early apoptotic death mechanism. 2020)/2020
•Cisplatin NPs are effective candidates to treat oral cancer.
In vitro •HNSCC cells treated with platinum chemotherapy-induced anti-tumor immunity, probably enhanced by anti-PD-1 (Park et al., 2019)/2019
therapy.
•Cisplatin, as the standard medication for HNSCC, seems to affect anti-tumor immunity as oxaliplatin in such
preclinical models.
In vitro •Combined chemotherapy with CKD-602 and cisplatin prevented proliferation and enhanced the apoptotic effects (Choi et al., 2019)/2019
on the three OSCC cell lines.
•The cell lines were found with Apoptosis, and there were remarkable synergistic effects of CKD-602 combined with
cisplatin despite the differences in p53 status.
•Combined chemotherapy with CKD-602 with cisplatin can be regarded as a possible therapeutic approach for
OSCC.
In vitro •Cylindromatosis (CYLD) down-regulation-induced Cisplatin resistance was found related to a mechanism, by which (Suenaga et al., 2019)/2019
the intracellular cisplatin accumulation was reduced and the cisplatin-related apoptosis via the NF-kB hyper
activation was suppressed.
•Also, the combined cisplatin and bortezomib therapy showed remarkable anti-tumor activities on CYLD down-
regulation-induced cisplatin resistance in SAS cells.
•Based on the results, loss of CYLD expression can induce cisplatin resistance in OSCC cases by NF-kB hyper
activation and may be linked to poor prognosis in OSCC cases.
Doxorubucin In vitro •Mesoporous silica nanoparticles (MSNP) are modifiable with cationic polymer polyethyleneimine for obtaining a (Wang et al., 2018)/2018
positively charged surface, enabling the MSNP for carrying MDR1-siRNA and DOX.
•According to the transfection efficiency methods, the MSNP-PEI-DOX/MDR1-siRNA showed effective transfection
into KBV cells in vitro. KBV cells transfected with MSNP-PEI-DOX/MDR1-siRNA decreased MDR gene expression and
induced the KBV cell’s apoptosis in vitro. MSNP-PEI-DOX/MDR1-siRNA significantly decreased the tumor size and
reduced the rate of tumor development than the control group in Vivo.
•Newly synthesized MSNP-PEI-DOX/MDR1-siRNA enhances the chemotherapy effectiveness to treat multidrug-
resistant cancer than the DOX only.
In vitro •Resveratrol combined with doxorubicin caused an additive augmentation of doxorubicin cytotoxicity in both cell (Sheng et al., 2018)/2018
types.
•Nevertheless, epigallocatechin gallate and tannic acid at a specific dose decreased the doxorubicin-related kera
tinocyte toxic effect principally because of decreased doxorubicin-related necrosis in normal human oral kerati
nocytes with no weakening of doxorubicin anticancer effectiveness.
•Although the underlying mechanism is uncertain, intracellular reactive oxygen species are not the only possible
factor.
In vitro •N1-guanyl-1,7-diaminoheptane (GC7, an eIF5A-2 inhibitor) or siRNA against doxorubicin were evaluated in OSCC (Fang et al., 2018)/2018
cell lines.
•Low level of GC7 remarkably increased doxorubicin cytotoxicity in epithelial phenotype OSCC cells (Cal27) as well
as mesenchymal phenotype OSCC cells (HN30 and Tca8113).
•EMT process enhanced through doxorubicin in Cal27 cells was reversed with GC7. Also, GC7 caused mesenchymal-
epithelial transition (Mazorra et al.) in HN30 and Tca8113 cells. The eIF5A-2 silencing with certain siRNA showed
the same effects.
•The synergistic cytotoxic effects of doxorubicin/GC7 was not caused in EMT driver TWIST1, silenced Cal27, HN30,
and Tca8113 cells.
•Moreover, GC7 synergized doxorubicin for inhibiting tumor development in vivo.
In vivo •Using Doxorubicin-loaded nanoparticles (n-Dox) showed no adverse effects on the white and red blood cell counts. (Khiavi et al., 2019)/2019
(Rats) •Thrombocytopenia and leukopenia in n-Dox-received animals were less compared with the other groups.
•Hemoglobin and hematocrit in groups receiving treatment showed no difference and showed similar levels as the
normal control group.
•The groups showed no significant difference in Hepatic and cardiac enzymes.
14
Synthetic Drugs
•A significant reduction was observed in hematological changes, such as leukopenia and anemia, in the 4-NQO-
induced OSCC animal model after using n-Dox compared to Dox.
•Using n-Dox was more effective to treat OSCC than Dox.
In vitro •This research aimed at assessing the apoptotic effect of doxorubicin and Doxil, its nano-formulated form, on OSCC (El-Hamid et al., 2019)/2019
CAL-27 cells.
•Doxil showed a greater apoptotic effect on CAL-27 cells than doxorubicin and increased caspase-3 concentration
more than doxorubicin. It exhibited a more inhibitory effect on C-Myc mRNA.
Docetaxel Clinical •Results of CCRT with cisplatin and DTX injection intravenously in cases with primary and advanced OSCC were (Sato et al., 2019)/2019
similar to those treated with standard CCRT for advanced HNSCC through intravenous injection. Also, the toxic
effects were lower compared with standard treatments.
•Therefore, this therapy is immune and effective to treat advanced oral cancer.
In vitro •The in vitro cytotoxic effects of drug-loaded NPs were assessed on human tongue carcinoma cell line SCC-9 (ATCC- (Srivastava et al.,
CRL-1629). 2018)/2018
•The in vitro investigations indicated anti-proliferative effects of PLGA DTX NPs than free DTX, dose-dependently in
response to SCC-9.
Clinical •The initial tumor response rate of 99.3% was reported (response rates: complete: 56.7%, good partial: 17.0%, and (Hasegawa et al., 2020)/2020
fair partial: 25.5%).
•Also, no severe AEs due to intra-arterial chemotherapy using DTX, cisplatin, and peplomycin in combination with
intravenous chemotherapy with 5-fluorouracil (IADCPIVF) were found.
•A 5-year OS rate of 74.6% was reported.
•The important prognostic factors were the multivariate analysis of survival, T classification, and clinical tumor
response.
•Therefore, 5-fluorouracil (IADCPIVF) can be used to treat OSCC.
5-Fluorouracil In vitro •5-FUNE/Cur-NE/5-FU-Cur-NE effectively produced and indicated the average rate of the particle size, surface (Srivastava et al.,
(5-FU) charge, and PDI. 2018)/2018
•In vitro 5-FUNE/Cur-NE/5-FU-Cur-NEs release was recorded within 04 days, and acidic pH showed a higher release
than alkaline pH, plus acceptable stability data.
•Studies on Cytotoxic effects have reported a higher anticancer activity dose-dependently with a lower IC50 value of
NEs than the Blank Nanoemulsion (BLNE).
•Studying Cellular uptake of 5-FUNE/Cur-NE/5-FU-Cur-NEs improved highly, comparatively BLNE showed the
possibility of cell arrest.
•Also, the Blc2, Bax, P53, and P21 expression was revised and increased cell apoptosis.
•Combination treatment of CUR and 5-FU loaded in the nanoformulation system showed anticancer activity to treat
oral cancer.
In vitro •The effectiveness of combination therapy using metformin and 5-FU to treat human OSCC in vitro and in vivo was (Harada et al., 2016)/2016
and in indicated.
vivo •Metformin and 5-FU effectively suppressed cell development and caused apoptosis in OSCC cell lines (HSC2, HSC3,
(nude and HSC4) than each agent alone.
mice) •It lowered the level of lactate in the metformin supernatants and 5-FU-treated cells than metformin- or 5-FU-treated
cells.
•This Combination therapy for 4 weeks was effective to reduce HSC2 tumor growth (77.6%) than metformin
(59.9%) or 5-FU (52%) alone in nude mice.
•Therefore, Combination therapy with metformin and 5-FU exerted a potent antitumor activity against OSCC by
inhibiting the Warburg phenomenon in tumor cells.
In vitro •NLRP3 inflammasome enhanced 5-FU resistance of OSCC in vitro and in vivo. Also, targeting the ROS/NLRP3 (Feng et al., 2017)/2017
and in inflammasome/IL-1β signaling pathway can be effective for 5-FU-oriented adjuvant chemotherapy of OSCC.
vivo
(mice
model)
In vitro •The combined epigallocatechin-3-gallate (EGCG) and 5-FU therapy decreased cell viability and migration distance (López et al., 2019)/2019
than the control groups and the same dose of 5-FU alone. Adding EGCG enhanced cell numbers in the G2/M phase,
whereas 5-FU arrested the cell cycle in the S phase.
•Also, 5 Gy radiation-exposed cells were less effective than being combined with EGCG.
•Therefore, the combined epigallocatechin-3-gallate (EGCG) and 5-FU therapy decreased cell viability, migration,
and changed the cell cycle to a greater extent compared with 5-FU alone.
In vitro •Oral cancer cells treated In vitro with 5-FU increased G1/S phase cells. (Li et al., 2004)/2003
•5-FU increased p21 expression but no significant changes were observed in p53 expression.
•A significant cyclin E up-regulation, as well as a simultaneous cyclin D down-regulation 24 h following 5-FU
treatment was found.
•Therefore, 5-FU-related alterations in cell cycle regulation of oral cancer cells are probably related to changes in G1
cyclins expression.
•A remarkable up-regulation of p21 was observed, however, its activity was supposed to be canceled due to an
increased binding to CDK4.
Methotrexate In vitro & •The effects of MTX on tumor cells in vitro and treatment response in 7 out of 10 cases were positively correlated. (Pai et al., 2009)/2009
(MTX) Clinical •A proof-of-principle pilot study suggested that oral cancer cells are associated with an intrinsically variable
response against MTX.
Clinical •MTX was delivered by a portable pump continuously through the external carotid artery within 5.5 days (range, (Wu et al., 2010)/2010
4–7 days), and it was continued by a bolus of low dose (25 mg/once a week) of MTX until stabilization of the clinical
condition.
•In the first week of intra-arterial infusion chemotherapy (IAIC), the tumors’ sizes were reduced.
•11 cases (61%) showed a complete clinical response and 7 cases (39%) were found with a partial clinical response,
after an average 26-month follow-up s (range, 8–72 months).
•The one- year survival rate was 87%, whereas and the three-year was 56%.
•No complication was reported because of the catheter.
15
Synthetic Drugs
•The mild and tolerable side effects were reported. IAIC is an appropriate option for the elderly with oral cancer with
co-morbidity because a radical surgery or extensive radiotherapy is avoided and provides a successful palliative
treatment in these cases.
In vivo •MTX Arginine (MTX-ARG) rats were found with greater jejunum and ileum weight, greater ileal mucosal weight, (Koppelmann et al.,
(Rats) greater ileal mucosal DNA and protein concentrations, greater villus height in jejunum and ileum, and crypt depth in 2012)/2012
the ileum, than MTX animals.
•MTX-ARG rats (versus MTX) showed a remarkable reduction in enterocyte apoptosis in the ileum along with
decreased Bax mRNA and protein expression and elevated levels of the BCL-2 protein.
•The mucosal injury was prevented after treatment with oral ARG. It also improved rat’s intestinal recovery after
MTX- injury.
Paclitaxel In vitro •Magnetized paclitaxel conjugate (M-PTX) enhanced apoptosis and G2/M arrest of cultured human oral cancer cell (Nakakaji et al., 2018)/2018
and in lines similar to PTX.
vivo •Also, magnetic resonance imaging of M-PTX showed significant contrast intensity.
(mice) •In a mouse model of oral cancer, a permanent magnet on the body surface near the tumor caused distinctive
accumulation of M-PTX, and the anti-cancer activity was more effective than M-PTX with no magnet.
In vivo •Animals treated with PTX loaded on gold nanoparticle (AuNPs) were found with significant outcomes than those (Asar et al., 2019)/2019
(Syrian treated with free PTX.
hamsters) •The distinctive AuNPs effects combined with the chemotherapeutic drug target OSCC and no adverse effects were
observed on the surrounding healthy cells.
In vivo •PKI166/PTX-received mice showed a significantly increased survival rate. (Holsinger et al., 2003)/2003
(Mice) •PTX and PKI166 prolonged survival in an orthotopic preclinical model of tongue cancer through an increase in
apoptosis of oral cancer.
In vivo •PTX inhibited the transplanted human OSCC development and decreased the immunohistochemical expression of (Myoung et al., 2001)/2001
(nude VEGF and CD31, as well as VEGF mRNA.
mice) •Thalidomide significantly decreased VEGF expression and CD31 and VEGF mRNA, however, it could not
significantly inhibit tumor development.
•Therefore, the growth of human OSCC cannot be merely associated with VEGF-related angiogenesis and that anti-
angiogenic therapy cannot treat OSCC effectively, however, it can be considered as an adjuvant chemotherapeutic
approach.
In vitro •This research aimed at determining the polyinosinic-polycytidylic acid (poly I:C) effects, a TLR3 agonist, oral (Park et al., 2012)/2012
cancer cell proliferation.
•TLR3 expression was observed in YD-10B and YD-8 cells.
•Using poly I:C suppressed cell growth concentration-dependently.
•According to Flow cytometry and Western blot analysis, poly I:C caused apoptosis through a mitochondria-
associated pathway.
•Also, poly I:C and PTX co-treatment remarkably suppressed cell proliferation than poly I:C or PTX alone.
considered with hepatic impairment. The maximum dose of DTX that a DOX in nanoparticles as tumor-targeted therapy reduces the damage of
human can tolerate is 100 mg/m2 every 21 days (Kenmotsu and Tani this drug to healthy cells. However, the combination of this drug with
gawara, 2015). Drug side effects can include poisoning by drug dose, nanoparticles enables specific effects on cancer cells by enhancing its
alopecia, mucositis, fatigue, sensory neuropathy, fluid retention, rash, antitumor activity (Li et al., 2009; Sadreddini et al., 2017; She et al.,
and hypersensitivity reactions (Fouad et al., 2019). Scientists have 2013).
suggested using nanoparticles to correct some of the disadvantages of
the drug. Chitosan scaffolds were found to improve the penetration of 5.5. Fluoropyrimidine 5-fluorouracil (5-FU)
the drug into the gastrointestinal tract (Ketabat et al., 2019). The use of
silver nanoparticles also led to the development of a suitable carrier 5-FU is an important anticancer drug due to its extensive antitumor
system for orally transferring DTX to cancerous tissues (Buch and Cha activity and high synergy with other anticancer drugs including oxali
tra, 2019). platin, and irinotecan. It is used as an intravenous drug for treating
different types of malignancies, including oral, colorectal, breast, and
5.4. Doxorubicin (DOX) head and neck cancers (Khan et al., 2019). It works by inhibiting RNA
synthesis and function, breaking down DNA strands, and inhibiting
Another effective anticancer drug, which is often used to treat thymidylate synthase activity. The disadvantages of this drug are its
various cancers and inhibits DNA and RNA synthesis, is Doxorubicin. very short plasma half-life of about 10–15 min and its rapid decrease in
Research has indicated that the Hedgehog (Chhaparwal et al.) signaling concentration, which lowers its efficacy (Iqbal and Pan, 2016). Various
pathway is important for tumor cell proliferation, migration, and methods, including the combination of this drug with other chemo
metastasis (Sharifzadeh, 2020). The pathway has also been activated in therapeutic agents, namely biochemical modulation, the use of nano
oral cancers (Fan et al., 2017), and targeting it can be a hopeful doorway particles, and its continuous infusion using ambulatory infusion pumps
for suppressing cancer cells. DOX has a therapeutic advantage over other have been suggested to compensate for these disadvantages. Continuous
drugs by targeting Hh signaling, but it also has some disadvantages, infusion pumps with indwelling catheters were not very positively
including the fact that its ability to increase cardiomyopathy and also welcomed because of increased hospital visits, and consequently,
drug tolerance limits its use in the treatment of various cancers (Tacar increased costs, and potential side effects of continuous infusion,
et al., 2013). Another disadvantage of the drug is its low permeability including gastrointestinal toxicity, myelosuppression, compromised
and release, as well as its effect on non-cancerous cells, which causes cell quality of life, dose modifications, and treatment delays (Iqbal and Pan,
death in major organs including the liver, kidney, and brain (Ketabat 2016; Ketabat et al., 2019). The oral form of this medicine is capecita
et al., 2019). Of course, it is possible to correct the disadvantages of DOX bine which is better than 5-FU in terms of prescription, efficacy, and rate
through nanoparticles to minimize its side effects and improve thera of action (Ljoncheva et al., 2020). Capecitabine can be used alone or
peutic efficacy. Various studies have shown that controlled release of with other chemotherapy drugs as well. The main advantage of
16
Fig. 5. (І) Various controlled drug delivery methods: (A) Intra-tumoral drug delivery; (B) local drug delivery; (C) photo-thermal therapies used in combination with
drug delivery systems; (D) ultrasound-mediated microbubble. (ІІ) Various carriers utilized for oral cancer: (A) polymeric nanoparticles; (B) nanolipids; (C) inorganic
nanoparticles; (D) hydrogels. Reprinted with permission from ref (Ketabat et al., 2019) with permission from MDPI.
capecitabine is its metabolic conversion to 5-FU at the tumor site for the induce apoptosis in oral squamous cells (Hu et al., 2015; Wang et al.,
maximum benefit of chemotherapy (Iqbal and Pan, 2016). Another 2020a). Oral administration of this drug is not recommended due to its
advantage of capecitabine is its mild toxicity and ease of use, which is low solubility and limited absorption capacity in the intestinal epithe
why it can be used to treat patients with recurrent head and neck cancer, lium, so it is mostly administered intravenously, with the disadvantages
especially recurrent or metastatic nasopharyngeal carcinoma patients of this method being its wide distribution in the body resulting in severe
(Zhang et al., 2010). side effects including liver dysfunction (Hu et al., 2015). The use of
nanoparticles has dramatically reduced these complications. For
example, conjugating PTX with chitosan nanoparticles not only in
5.6. Paclitaxel (PTX) creases the solubility of PTX in water but also increases its stability time
in the gastrointestinal tract (Ketabat et al., 2019). Using PTX nano
Paclitaxel is known to be one of the important antitumor drugs, emulsion formulas is another suggested method for improving the
which can inhibit DNA synthesis and protein transcription and thus bioavailability of oral PTX. Using the montmorillonite-PLGA nano
function through cell cycle inhibition (Hu et al., 2015). The drug particles is also one of the proposed methods that will increase the up
mechanism of PTX is through interaction with microtubules, which take of PTX in the target tissue cells and increase the PTX stability time
blocks the progression of mitosis by stabilizing microtubules in cells and in the gastrointestinal tract (Dong and Feng, 2005).
inhibits dynamic skeletal processes (Wang et al., 2013). PTX is also able
to inhibit cancer cell proliferation through the EGFR signaling pathway.
Targeting the EGFR signaling pathway is one of the potential therapeutic 5.7. Methotrexate (MTX)
targets in oral cavity cancer (Wang et al., 2020a). Studies have shown
that PTX can suppress cells involved in oral cancer depending on the Methotrexate is one of the first drugs discovered for chemotherapy in
time of administration and the dose that is administered, and thus various cancers. It is a folate antagonist that prevents the proliferation of
17
cancer cells by inhibiting the synthesis of purine and pyrimidines. It is promising therapies are also currently in the phase of laboratory studies,
used to treat different types of cancer including oral cancer, acute while the use of such safe methods for the treatment of oral cancer is
lymphocytic leukemia, head and neck cancer, non-Hodgkin’s lym essential. Furthermore, it is hoped that their scoring will be taken more
phoma, osteosarcoma, and choriocarcinoma (Jin et al., 2018). It is seriously, and they can be used to save the lives of thousands who are at
readily absorbed by the cells and is efficacious through rapid poly the risk of death each year.
glutamylation and the inhibition of the dihydrofolate reductase enzyme,
which is especially important for inhibiting cell proliferation. The sys Author contribution
temic bioavailability of this drug is about 70% injectable, which is
significantly higher than its oral route (Ketabat et al., 2019). If taken The authors declare that this work was done by the authors named in
orally, in addition to low systemic bioavailability, it is associated with this article. Seyed Ali Mosaddad, Hamid Tebyanian, and Farzaneh Gol
many side effects, including gastric injury, watery stool, ulcerative sto feshan were involved in study design and data collections. Seyed Ali
matitis, and hemorrhagic enteritis. The aforementioned factors led sci Mosaddad, Kimia Beigi, Maral Haghnegahdar, Tayebeh Doroodizadeh,
entists to develop solutions for oral administration of MTX without Reza Ranjbar, and Hamid Tebyanian were involved in critically
causing any side effects. One of these solutions is the use of solid lipid reviewing the data and help in writing the review article.
nanoparticles (SLNs). In one study, MTX was loaded into SLNs
comprised of glycerol monostearate, tristearin, compritol 888 ATO and Funding
stearic acid and sent to the target site. The results showed that SLNs
protected MTX, prevented gastric cell destruction and gastric damage There was no financial support.
and also dramatically increased MTX bioavailability (Paliwal et al.,
2009). Ethical approval
6. Conclusion This article is a review and does not contain any studies with humans
or animals performed by any of the authors.
Cancer is on the rise in different societies, endangering the lives of
millions of people annually. While treatments such as surgery and Declaration of competing interest
chemotherapy do not bring about dramatic chances of survival, they
affect both the patient’s health and quality of life. Consequently, it is The authors declare that they have no competing interests.
necessary to consider low-risk therapies or provide solutions to reduce
health risks. Despite the great influence of and dependence on modern Acknowledgment
medicine and the dramatic advances in the production of synthetic
drugs, relies a great many people in the world still depend on drugs The authors would like to acknowledge the useful comments were
made from herbs. According to the WHO, more than seventy-five given by colleagues at the Research Center for Prevention of Oral and
percent of people in the world rely on plants and their extracts for Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran,
health care needs. Many of the herbal ingredients used are cheaper and Iran.
more effective than modern drugs, surgeries, and chemotherapy against
specific diseases. Research shows that using herbal remedies is References
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Aplicações Terapêuticas de Fitoterápicossintéticosbiomedicamentos No Câncer Bucal Uma Atualização

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European Journal of Pharmacology 890 (2021) 173657

Contents lists available at ScienceDirect

European Journal of Pharmacology

Therapeutic applications of herbal/synthetic/bio-drug in oral cancer:

3. Herbal drugs 3.1. Curcumin

• No toxicity was observed in normal cells.

3.4. Garcinia indica substance (Dariya et al., 2019).

Fig. 4. (A) CT before treatment: a stable

Cisplatin In vitro •YC-1 (Lee et al., 2017)/2017

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