Grants and Contracts Details
Principal Investigator/Program Director (Last, first, middle): Damodaran, Chendil Project Summary Our research focuses on natural compounds that possess chemotherapeutic and/orchemopreventive properties with respect to cancer. In the proposed study, we will characterize themechanism of action of the compound Withaferin-A (WA) , a bioactive compound of Withania somnifera, which is extensively used in Asian and African traditional medicine. WA displays impressive and selective activity against androgendependent and androgen-independent prostatecancer (ADPC and AIPC, respectively), of which the latter is refractory to all current forms oftreatment. Our preliminary in vitro and in vivo data indicate WA targets ADPC and AIPC cells by inhibiting the activity of Akt, a protein kinase that activates cell survival pathways. Our preliminary data demonstrate that, concomitant to Akt inhibition in ADPC and AIPC cells, WA activates FOX03a, which inturn activates prostate apoptosis response-4 (Par-4), a protein that selectively induces apoptosis in cancer cells Based on our results, we hypothesize WA overrides the negative effects of Akt on CREB/Par-4 signaling to achieve chemopreventive and/or chemotherapeutic effects on AIPC. To address this hypothesis, we propose the following aims: investigate the interaction between AktlCREB and Par-4 signaling, (Aim 1); and how WA modulates the pro-apoptotic signaling in AIPC (Aim 2); evaluate the effects of WA on androgen- -independent prostate tumor growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) model (Aim 3); and examine the mechanisms of WA-mediated tumor inhibition in TRAMP and/or TRAMP cell lines (Aim 4). For the in vitro arm of our studies we will use a variety of approaches (immunoprecipitation, siRNA strategies, immunofluorescence, Western blot, Northern blots, Chip assays, siRNA strategies, pulldown assays, pharmacological blocking) in order to determine the molecular junction at which AktlCREB 3aand Par-4 converge. For our in vivo studies, we will conduct tumor regression studies, yet we will also examine histopathology, cell death, expression patterns of pro-survival proteins and pro-apoptotic proteins in the tumor tissues, and WA levels in the serum and prostate tissue. Our long term goal is to promote natural compounds to a clinical environment, where these agents can be thoroughly assessed for their chemopreventive and chemotherapeutic properties. Our preliminary data indicate WA is a potential candidate for such clinical evaluation, and our proposed studies will elucidate at a mechanistic level its potency against prostate cancer, both from a chemopreventive and chemotherapeutic standpoint. Project Description Page 6
|Effective start/end date||8/1/10 → 5/31/11|
- National Cancer Institute: $45,783.00
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