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Constitutive over expression of Akt has been implicated in de novo resistance to current treatments in many cancer types including breast cancer. Akt mediates a variety of biological responses and is associated with a poor prognosis in breast carcinoma resulting in resistance to hormone -, radiation- and chemo-therapy. Our research is focused on exploring the role of a natural dietary compound, Diosgenin (a major constituent of fenugreek) in Akt signaling and its ability to sensitize breast cancer cells in vitro and in vivo models. Inhibition of Akt kinase activation resulted in the downregulation of its downstream targets (Raf, MEK and ERK) in breast cancer cells. Also, inactivation of NFκB and downregulation of Bcl-2 resulted in an induction of caspase activation in breast cancer cells. The complete inhibition of pro-survival signaling by disogenin resulted in cell cycle arrest and induction of apoptosis in breast cancer cells. Additional studies revealed a downregulation in G1 cell cycle regulatory proteins - cyclin D1 and cdk-4 following treatment with Diosgenin in a time dependent fashion. Interestingly, diosgenin had minimal toxicity in normal breast epithelial cells, MCF-10A, showing that it specifically targets cancer cells sparing the normal cells. In vivo studies suggested that diosgenin significantly inhibited tumor growth in both MCF-7 and MDA-231 xenografts in nude mice. Our results suggest that diosgenin can be used as a potential chemopreventive or chemotherapeutic agent for breast cancer.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA