Naturally-occurring dimers of flavonoids as anticarcinogens

Biflavonoids are dimers of flavonoid moieties linked by a C-C or C-O-C bond. Simple, complex, rearranged, natural and ketalized Diels-Alder adducts, benzofuran derivatives, and spirobiflavonoids are some of the structural groups of biflavonoids. These compounds are mainly distributed in the Gymnosperms, Angiosperms (monocots and dicots), ferns (Pteridophyta), and mosses (Bryophyta). Biflavonoids have shown a variety of biological activities, including anticancer, antibacterial, antifungal, antiviral, antiinflammatory, analgesic, antioxidant, vasorelaxant, anticlotting, among others. This work is focused on probably the most potentially relevant biological activity of biflavonoids, the anticancer activity and the involved mechanisms of action, such as induction of apoptosis [inhibition of cyclic nucleotide phosphodiesterases; effects on NF-κB family of transcription factors; activation of caspase(s); inhibition effects on bcl-2 expression, and upregulation of p53 and caspase-3 gene expression]; inhibition of angiogenesis [anti-proliferative effects; activation of Rho-GTPases and ERK signaling pathways; inhibition of FASN activity]; inhibition of pre-mRNA splicing; inhibition of human DNA topoisomerases I and II-α; anti-inflammatory/ immunoregulatory effects [inhibition of XO; inhibition of proinflammatory enzymes, such as PLA2 and COX; effects on cytokines mediated COX-2 and iNOS expression]; modulation of immune response; inhibition of protein tyrosine phosphorylation; antioxidant and analgesic activities in relation to the anticarcinogen behavior. For that reason the structures and anticarcinogenic activities of 83 biflavonoids are thoroughly discussed. The results of this work indicate that biflavonoids strongly affect the cancer cells with little effect on normal cell proliferation, suggesting a therapeutic potential against cancer.