Flavonoids and Cancer
In collaboration with Prof. Brandon White’s laboratory in the Department of Biological Sciences at San Jose State University, we are endeavoring to understand the molecular mechanisms behind the healthful properties of the flavonoid class of plant natural products. Numerous published reports have suggested that flavonoids are selectively toxic to cancer cells1 but the precise mechanism of this activity is not well understood. Since flavonoids are known to be antioxidants, several researchers have proposed that the protective effects of the flavonoids are based on this property. However, flavonoids have also been reported to modulate the activity of a number of cellular signaling pathways.2 Which of these activities is responsible for the healthful effects?
We are engaged in a project aimed at deconvoluting this complex biology by preparing a series of flavonoid analogues via chemical synthesis each of which possesses a subset of the natural flavonoids activities. By evaluating the effect of these analogues on cultured cells, both cancerous and normal, we hope to identify activities that are both necessary and sufficient for the selective cytotoxicity towards tumor cells.
Image courtesy of Prof. Thomas Kurtzman, Dept. of Chemistry, Lehman College
An interesting recent discovery3,4 that complicates the analysis of the mechanism of flavonoid bioactivity is the observation that several flavonoids inhibit members of the caspase family of cysteine proteases. Since caspases are necessary for cellular apoptosis and the flavonoid-induced selective tumor cytotoxicity has been attributed to apoptosis, this result raises the question of whether tumor cell death in response to flavonoids has been correctly characterized.
Since the ability to inhibit caspases selectively has potential therapeutic utility for degenerative diseases and inflammation, we are also engaged in a collaboration with Prof. Thomas Kurtzman in the Chemistry Department at Lehman College to design, synthesize, and test synthetic flavonoid analogues that are able to effect selective and potent caspase inhibition.
(1) Ramos, S. Journal of Nutritional Biochemistry 2007, 18, 427-442.
(2) Williams, R. J.; Spencer, J. P. E.; Rice-Evans, C. Free Radical Biology and Medicine 2004, 36, 838-849.
(3) Shimmyo, Y.; Kihara, T.; Akaike, A.; Niidome, T.; Sugimoto, H. Journal of Neuroscience Research 2008, 86, 1836-1845.
(4) White, J. B.; Beckford, J.; Yadegarynia, S.; Ngo, N.; Lialiutska, T.; d'Alarcao,
M. Food Chemistry 2012, 131, 1453-59. [html]