Resveratrol and Colorectal Cancer: Focus In vitro , In vivo and Clinical Assays

Resveratrol is a natural non-flavonoid polyphenol present in different plants such as grapes, peanuts, soybeans and berries, which has beneficial effects on humans due to its anti-inflammatory, antioxidant, neuroprotective, cardioprotective and cancer prevention action. Since the effects of resveratrol in vitro on different tumors are significant, its application in the prevention of colorectal cancer can have a positive impact, since resveratrol can be consumed by eating natural foods. However, its effects in experimental models using chemical carcinogens and in clinical trials with humans in the prevention of colorectal cancer have been shown to be inconsistent, largely due to its low aqueous solubility and bioavailability. To overcome these problems, new formulations containing resveratrol have been used to promote increased solubility, bioavailability and therapeutic effect in cancer prevention. Abbreviations:


Mini Review
Resveratrol (3,40,5-trihydroxy-trans-stilbene) is a natural stilbene and non-flavonoid polyphenol present in more of 70 plants species, including peanuts (Arachis hypogaea), Japanese knotweed (Fallopia japonica), grape vine (Vitis vinifera) and foods such as wine, soy, Itadori tea, and red fruits. Resveratrol is a natural compound whose use has been described in the treatment and prevention of different diseases such as inflammatory, cardiovascular, neurological disease and cancer [1]. Resveratrol has in vitro cytotoxic effects against lymphoid and myeloid tumors, breast, skin, cervix, ovary, stomach, prostate, liver, pancreas, thyroid and colon tumors [2]. Its antitumor effects have been associated with different mechanisms, such as interruption of cell cycle and induced of apoptosis; inhibition of nitric oxide synthase expression; antioxidant effect with inhibition of lipid peroxidation and DNA damage; inhibition of the cyclooxygenase pathway of arachidonic acid metabolism; and procarcinogen bioactivation and carcinogen detoxification [3].
Resveratrol alters the activity of cyclin-dependent kinases and the cell cycle in the G0/G1 phase, and activation of the p53-dependent pathway, limiting the tumor growth [4,5]; and inhibits anti-apoptotic proteins of Bcl-2 family and activates proapoptotic proteins like Bad, Bak, Bax, PUMA, Noxa and Bim [6].

Colorectal Cancer
Approximately 90 to 95% of cancer cases described in humans are related to lifestyle, diet, pollution and obesity [10], where colorectal cancer corresponds to the third most frequent cancer in men, behind prostate and lung cancer. Colorectal cancer has an important relationship with lifestyle and diet rich in red meat and processed meat, low content of non-absorbable vegetable fibers, high content of refined carbohydrates, alcoholism and smoking [11]. Colorectal cancer has a peak incidence between 60 and 70 years of age, with worldwide distribution and greater incidence in the United States, Canada, Australia, New Zealand, Denmark and Sweden [12,13] The antitumor effect of resveratrol has been described in vitro in different colorectal cancer cell lines, such as HT-29 [14], LoVo [15], oxaliplatin-resistant colorectal cancer cells (HCT116/L-OHP) [16], human colorectal cancer stem cells [17], parental CRC cell lines (HCT116, SW480) and their isogenic 5-FU-chemoresistant clones (HCT116R, SW480R) [18] and cisplatin-resistant colorectal cancer cells HCT-116 [19]. In the process of colorectal carcinogenesis, there are two distinct pathways, the APC/β-catenin pathway (adenoma-carcinoma sequence) and the mismatch repair pathway  [26] or prostaglandin E 2 levels in intestinal cells [27]. Epidemiological studies in humans demonstrated that consumption of grape was associated with lower risk development of different kinds of cancer [28], including breast [29] and head and neck carcinoma [30].
In patients with colorectal cancer, the oral use of resveratrol was demonstrated a lower diminish on proliferative cancer cell activity [31]; moderate decrease in the Wnt/beta-catenin pathway in the intestinal crypt floor, critical pathway to maintenance of stem cells, and involvement in development of colorectal cancer [32]; relative increase of apoptosis on metastatic cells [33]; and reduction of plasma levels of insuline-like growth factor I (IGF1) and binding to insulin-like growth factor-binding protein-3 (IGFBP3), that regulate cancer progression and metastasis [34]. These limited and unsatisfactory results, in addition to the publication of a study that did not describe any beneficial effect of resveratrol on mortality associated with cancer [35], raised doubts about its real benefits in the face of cancer. These results may be associated with different types of study, tumor models and dose of resveratrol. Resveratrol is an extremely photosensitive compound with low chemical stability, low aqueous solubility and bioavailability, leading to a plasma halflife of 8 to 14 minutes, where the primary molecule is metabolized and converted into other secondary compounds with a half-life of 9.2 hours, such as sulfate conjugate, leading to a low therapeutic potency [36].

Discussion
Resveratrol has significant antitumor activity in vitro due to its ability to promote decreased prostaglandin E 2 synthesis; diminish of oxidative stress; bioactivation of procarcinogens and detoxification

Conclusion
Optimizing the chemical stability and solubility of resveratrol can make it have great potential in preventing colorectal cancer.