Natural polyphenols are secondary metabolites of plants involved in defense against different types of stress. Extracts containing these compounds have been used for thousands of years in traditional eastern medicine. Polyphenols act on multiple targets in pathways and mechanisms related to carcinogenesis, tumor cell proliferation and death, inflammation, metastatic spread, angiogenesis, or drug and radiation resistance. Nevertheless, reported effects claimed for polyphenols are controversial, since correlations between in vitro effects and in vivo evidence are poorly established. The main discrepancy between health claims versus clinical observations is the frequent use of nonphysiologically relevant concentrations of these compounds and their metabolites in efficacy and mechanistic studies. The present review will discuss how in vivo administration correlates with polyphenol metabolism, toxicity, and bioavailability. Analysis of the general application of polyphenols in cancer therapy will be complemented by potential applications in the therapy of specific tumors, including melanoma, colorectal and lung cancers. Possible pharmaceutical formulations, structural modifications, combinations, and delivery systems aimed to increase bioavailability and/or biological effects will be discussed. Final remarks will include recommendations for future research and developments.

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Colorectal cancer is one of the most common malignancies worldwide. The treatment of advanced colorectal cancer with chemotherapy and radiation has two major problems: development of tumor resistance to therapy and nonspecific toxicity towards normal tissues. Different plant-derived polyphenols show anticancer properties and are pharmacologically safe. In vitro growth of human HT-29 colorectal cancer cells is inhibited (f56%) by bioavailable concentrations of trans-pterostilbene (trans-3,5-dimethoxy-4 ¶-hydroxystilbene; t-PTER) and quercetin (3,3 ¶,4 ¶,5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols. I.v. administration of t-PTER and QUER (20 mg/kg  day) inhibits growth of HT-29 xenografts (f51%). Combined administration of t-PTER + QUER, FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil; a first-line chemotherapy regimen), and radiotherapy (X-rays) eliminates HT-29 cells growing in vivo leading to long-term survival (>120 days). Gene expression analysis of a Bcl-2 family of genes and antioxidant enzymes revealed that t-PTER + QUER treatment preferentially promotes, in HT-29 cells growing in vivo, (a) superoxide dismutase 2 overexpression (f5.7-fold, via specificity protein 1-dependent transcription regulation) and (b) down-regulation of bcl-2 expression (f3.3-fold, via inhibition of nuclear factor-KB activation). Antisense oligodeoxynucleotides to human superoxide dismutase 2 and/or ectopic bcl-2 overexpression avoided polyphenols and chemoradiotherapy-induced colorectal cancer elimination and showed that the mangano-type superoxide dismutase and Bcl-2 are key targets in the molecular mechanism activated by the combined application of t-PTER and QUER. [Mol Cancer Ther 2008;7(10):3330 -42]

Solar radiation exposure is the chief cause of nonmelanoma (i e, basal cell and squamous cell) skin cancer, and it is also a prime factor in the etiology of cutaneous melanoma The cancer-causing effects of ultraviolet (UV) radiation on the skin are mainly produced by UV-B radiation in the 290- to 320-nm range, the same range that produces burning in human skin (erythema) UV-B exposure can damage DNA and be immunosuppressive Thus, and considering the alarming numbers of skin cancers being diagnosed around the world, it is increasingly evident the need of effective protection from UV radiation Resveratrol (trans-3,5,4′-trihydroxystilbene; RES) is a phytoalexin present in a wide variety of plant species, where its synthesis is induced by stress conditions The cancer chemopreventive activity of RES was first reported by Jang et al [Science 275, 218 – 220 (1997)] in a model of skin carcinogenesis where topic administration of this polyphenol inhibited multistage mouse skin carcinogenesis Equally promising action is exerted by resveratrol analogues, mainly pterostilbene (3,5-dimethoxy-4′-hydroxy-trans-stilbene: PTER), which shows a higher half-life in vivo and more potent anticancer effects in vivo than RES Our aim was to compare the anticancer effects of RES and PTER in UVB-induced mouse skin carcinogenesis In our experiments, Female SKH-1 hairless mice were irradiated with UVB (180 mJ/cm2; 3 doses/week; for a total of 30 weeks) 20 min after or before the topical administration of liposomes containing a total of 10 μmol of RES or PTER/mice (aprox 2 5 μmol/cm2 of skin) This long-term UVB administration reproduces, in an animal model, which are the consequences in humans of receiving chronic UVB radiations We observed that pretreatment of the skin with PTER resulted in a dramatic reduction in UVB-induced skin tumorigenesis (90 % of tumor free-mice at the end of treatment, n=20; P<0 01), whereas all RES-treated mice showed carcinomas (0 % of tumor free-mice on the 30th week, n=20) Molecular mechanisms involved in this strong anticancer effect elicited by Pter (as compared with RES) suggest differences in prevention of DNA mutagenesis, and protein and lipid oxidation Our results indicate that PTER can be used efficiently in the prevention of skin carcinogenesis induced by solar radiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4239. doi:10.1158/1538-7445.AM2011-4239