Cancer is a major cause of mortality and is characterized by uncontrolled cell division of abnormal cells in a small area of the body, where programmed cell death and proliferation are imbalanced. (1) Despite the significant advances and milestones achieved in cancer treatment modalities, both incidence and mortality rates are disappointingly still high and has not decreased in the last 30 years, (2) thus urging more research for developing more effective and less toxic treatment approaches. (3)
Traditional chemotherapy is effective, but it also has a number of side effects that may be dose-limiting, meaning that their severity could force cancer treatment to come to a halt. (1) Furthermore, owing to the non-specific nature of chemotherapeutic drugs, not all malignant cells are always destroyed from the body, which might lead to tumor recurrence. (4)
Because of the severe limitations of traditional therapy, oral cancer chemoprevention is currently a research focus, and this interest has markedly increased with the improvement in illustration of the biology of carcinogenesis and identification of possible molecular targets involving this process. (5) Complementary medicinal preparation can be utilized to target specific cancer cells in order to inhibit tumor growth, metastasis, and progression without causing major adverse effects. (6, 7)
Discovery of the naturally occurring plant based compounds called phytochemicals has facilitated the development of new treatment strategies for patients that are at risk for, or have developed head and neck SCC. (8)
Phytochemicals are bioactive compounds produced by plants in their primary or secondary metabolism to protect them from external threats, thereby aiding in their development and reproduction. Spices, fruits, vegetables, and other plant species naturally contain dietary phytochemicals. (8) A meta-analysis of several observational studies found that diets high in plant-based foods have a negative correlation with cancer risk in general and can be used in cancer chemoprevention. (9,10)
Plant consumption containing highly potent phytochemicals can be less expensive and convenient than surgery and chemotherapy when compared to conventional cancer treatments. (11) Consequently, phytochemicals are promising adjuvants which help to decrease the incidence of cancer so decrease the financial medical expenses in developing societies. (1)
Researchers are interested in the anticancer efficacy of a wide range of plants against various types of carcinomas. A vast number of natural compounds have been investigated for their ability to cause apoptosis in human cancer cells. (12) These substances are high in polyphenols, which have anti-oxidant, anti-migratory, anti-proliferative, and anti-invasive effects on cancer cell properties, and are thought to inhibit carcinogenesis by acting on downstream signaling pathways. (13)
While there are many compounds that have been studied, the compounds from a specific category of phytochemicals, phenolics (resveratrol, EGCG, curcumin, quercetin, and honokiol), are emerging as potent and effective inhibitors of oral carcinogenesis. These compounds have been shown to inhibit head and neck SCC growth through different mechanisms. (13)
Research has demonstrated that these compounds can regulate cancer cell proliferation by regulation of multiple cell signaling pathways. They can impede cell cycle progression, induce differentiation and apoptosis, inhibit angiogenesis, and inhibit cancer cell invasive and metastatic properties. They can protect normal cells during treatment and reduce the damage caused by chemotherapy and radiotherapy. (14)
Green tea has shown scientifically proven useful medical advantages. Polyphenols account for 36% of the dry tea leaf weight, as well as glycosides, leucoanthocyanins, and phenolic acid. Catechins are a group of polyphenols that include (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC). (15)
Green tea has been shown to have antiviral, anti-inflammatory, and antiallergic properties. (16) The first report of EGCG's cancer-preventive activity was published in 1987, (17) and since then, the importance of EGCG and green tea in cancer prevention and therapy has become widely recognized. (1, 18) Green tea polyphenols have been shown to inhibit various pathways linked to cancer cell growth, survival, and metastasis. (1)
Curcumin, a natural polyphenol, is one of the most investigated biomolecules from Mother Nature. Curcuma longa or turmeric, its natural source, has been utilized in Indian ayurvedic and siddha medicine, as well as Chinese medicine, for thousands of years. (19)
Curcuma longa has been shown to have anti-inflammatory properties in animal models, with curcumin playing a key role. Because of its phenolic composition, curcumin also serves as an antioxidant. This substance affects glutathione and peroxidase activity in the blood, reduces lipid peroxidation, and scavenges reactive oxygen species. (12)
Curcumin's anti-tumorigenic and chemopreventive properties are its most important properties. Curcumin administered orally or topically, was found to dramatically reduce DNA adducts in a study on turmeric and oral cancer. (20) In peripheral cells, curcumin successfully repairs damaged DNA strands. It also deactivates the carcinogens found in tobacco. (21)
Furthermore, “combination chemoprevention”, which can not only increase the potential synergistic efficacy of medications, but also reduce the toxicity of the individual agents, with a lower dose treatment in a combination regimen, is a significant consideration. (22) Pointing to the evidence that the primary pathways targeted by these drugs have a crosstalk, (23) chemopreventive agents exert their action through a diversity of mechanisms including induction of apoptosis, cell proliferation suppression and angiogenesis inhibition. (24)
The apoptotic process can be modulated by dietary chemopreventive substances. (25) Angiogenesis (the development of new blood vessels) is a complex vital process involving angiogenic substances generated by cancer cells and immune cells. It has been linked to the progression, aggressiveness and metastases of various cancers including oral squamous cell carcinoma (OSCC). (26)
Given these multiple lines of evidence, we hypothesized that a combination of these two agents may provide effective chemoprevention through synergistic effect on the apoptotic pathways and other targeted oncogenic (angiogenic and proliferative) pathways. In this study, 7,12-dimethylbenz(a)anthracene (DMBA), induced oral carcinogenesis animal model was used as a system to assess efficacy of the combination of green tea and curcumin in chemoprevention at the preclinical level.