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Radio-Sensitizing Effects of Novel Histone De-Acetylase Inhibitors in Prostate Cancer

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Annual summary 1 Sep 2004-31 Aug 2005

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In the proposal, we hypothesized that HDAC inhibitors will sensitize the effects of ionizing radiation IR through inhibition of pro-survival events with simultaneous up-regulation of pro-apoptotic events. The following three specific aims were proposed Aim 1. To determine the combined effects of HDAC inhibitors and ionizing radiation on prostate cancer cell lines PC-3, LN-3, LnCAP, DU-145 and 22Rv1. Aim 2. To understand the signaling pathways induced by combined exposures to IlDAC inhibitors and ionizing radiation in both androgen dependent and independent prostate cancer cell lines. Aim 3. To determine the combined effects of HDAC inhibitors plus ionizing radiation on the regression ofi prostate cancer xenografts PC-3 in nude mice and ii in-situ prostate tumor in TRAMP mice. The following tasks were achieved Aim 1 The radiosensitizing effects of VADS-l8 and VAD-20 were studied in PC-3 cells. Further, due to change in the inhibitors for the remaining part of the grant, effects of SAHA and S-HDAC-42 were investigated in PC-3, LN-3 and DU-145 cells. S-HDAC-42 could sensitize PC-3 cells to radiation. Aim 2 Effects of VAD-18 and VAD-20 were mediated through cell cycle arrest, down-regulation of anti-apoptotic proteins, up-regulation of pro-apoptotic proteins and abrogation of radiation-induced nuclear translocation of p65, thereby, enhancing cell death. Aim 3 The breeding of TRAMP mice is in progress. We are currently increasing the population of true TRAMP mice for further experiments. Ultrasound Imaging protocol will be used for assessing in situ regression of tumors.

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  • Medicine and Medical Research

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