cdc42 inhibitor Conclusions can be made from many

Conclusions can be made from many in vitro studies including those mentioned above that citrus flavonoids exert strong anti-cancer activities. However, the beneficial effectiveness of a drug or a nutrient can only be attested by in vivo efficacy studies. In this review, we summarize the in vivo anti-cancer effect of bioactive compounds either as single cdc42 inhibitor or as a mixture of molecules from citrus peels. The anti-cancer activity of citrus peel flavonoids has been evaluated on several animal models, including cancers of skin [17,29], colon [30–34], prostate [33,35], lung [36], and liver [37] among others.
Citrus flavonoids and their biological activity Citrus and citrus peels contain common flavonoids, such as hesperidin, naringin, neohesperidin, narirutin, eriocitrin, didymin and rutin among others [27,46,47]. A number of studies have demonstrated the biological properties of these citrus flavonoids including anti-carcinogenic, anti-oxidant and anti-inflammatory properties that promote and benefit human health [46–49]. In addition to citrus flavonoids, citrus peels are also the sole and rich source of polymethoxylated flavonoids, which were found to exert many biological properties, particularly anti-cancer and anti-inflammatory activity [1,4,5,7]. Recent studies have also demonstrated potent anti-carcinogenic and anti-inflammatory efficacy of 5-demethylated polymethoxyflavones in single molecules [5,50,51] or in multiple 5-demethylated polymethoxyflavones [52]. The natural content of 5-demethylated polymethoxyflavones in citrus peels is low in percentage, but it has been confirmed that they have more potent biological activity than their non-demethylated counterparts, such as anticancer activity [50–52]. In essence, there are three subclasses of citrus flavonoids exiting abundantly in citrus peels, namely, polyhydroxyflavonoids, polymethoxyflavonoids and mixed substituted flavonoids with both hydroxyl and methoxyl groups, particularly 5-demethylated polymethoxyflavnoids. These flavonoids have demonstrated effective anti-cancer property both in vitro and in vivo, either in a form of individual compounds or in a mixture of citrus flavonoids. The anti-cancer study of these flavonoids has progressed well in recent years owing albeit in the initial steps to the modern chemical analysis and isolation and the biological activity testing. However, with the exception of nobiletin, the relationships between each individual flavonoid in citrus peels and its bioactivity such as anti-carcinogenesis remain untouched to some extent. Relationships among the naturally proportioned flavonoids in citrus peels and their biological activities are even more complex and unexplored.
Conclusion In summary, the in vivo studies provide compelling evidence that flavonoids from citrus peels, such as nobiletin and citrus peel extract (CPE) demonstrated potent anti-tumor activities in cancers of skin, colon, prostate, lung and liver. The therapeutic mechanism may include inhibition of inflammation, proliferation, angiogenesis, and induction of apoptosis. A characteristic and unusual feature of flavonoids from citrus peels is their high concentration of a diverse assortment of polyhydroxylated flavonoids, polymethoxyflavones, and other flavonoids. Nobiletin, a representative of citrus polymethoxyflavones, expressed potent efficacious activity against carcinogenesis. In view of other studies examining the impact of individual flavonoids such as polyhydroxylated flavonoids (PHFs) or polymethoxyflavones (PMFs) and related flavonoids [1], it is possible that the biological properties of mixed flavonoids from citrus peels summarized above are due to an additive or synergistic interaction of the complex mixture of phytochemicals, which may provide enhanced anti-cancer efficacy. The detailed mechanisms by which these flavonoids in citrus peel exert optimal benefits remain to be further elucidated. However, the evidence presented in this review illustrates that citrus flavonoids could prove to be an effective anti-cancer agent, especially against skin, colon, prostate, lung and liver cancer and encourage future research to evaluate its efficacy in human clinical trials.