( cientific Officer. Information relate...)VioQuest Pharmaceuticals Announces Data Presentation for Its Akt,Inhibitor VQD-002, at American Association for Cancer Research,Annual Meeting,Health

Information related to the presentations is as follows:

Abstract Number: 5399: Prostate cancer (PCa) is one of the most common malignancies in humans and the second leading cause of male cancer death in America. Prostate cancer mortality results from metastases to bones and lymph nodes and progression from androgen-dependent to androgen-independent disease. Therapeutics for these aggressive forms of cancers are lacking. Previously, we reported that the cyclin dependent kinase inhibitor (CDK) roscovitine down- regulates the expression of X-linked Inhibitor of Apoptosis (XIAP) in metastatic PCas and can induce cell death of PCas that express functional p53. In this study, we found that roscovitine can inhibit cell growth, reduce colony formation and induce apoptosis in PC3 and PC3-M cells that are p53 negative, when co-cultured with either LY294002 (LY) or Triciribine (also known as small molecular Akt/Protein Kinase B signaling Inhibitor-2 (API-2)), which are inhibitors of Akt. Neither roscovitine nor LY or API-2 by itself is sufficient to induce apoptosis of these tumor cells. Further, apoptosis induced by the combination treatment was inhibited by pre-treatment of PC3 cells with a pan-caspase inhibitor and caspase-3 and -9 inhibitors, but not a caspase-8 inhibitor, suggesting that the combination induce the mitochondrial pathway of apoptosis. However, the above combination treatment, when added to RWPE cells for 20 hours, had very little effect, suggesting that the combination treatment is not toxic to normal prostate epithelial cells. In PC3 cells, roscovitine reduced abundance of XIAP but not Mcl-1, whereas API-2 induced Bim. The effect of roscovitine was mimicked by depletion of Cdk9, but not Cdk7 by RNA interference. Moreover, depletion of XIAP or Cdk9 by RNA interference was sufficient to sensitize PC3 and PC-3M cells towards API-2 and induce apoptosis. Collectively, these studies suggest that combined inhibition of Cdk9 and Ak
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