Radio-sensitizing Effects of Novel Histone De-Acetylase Inhibitors in Prostate Cancer
Abstract
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 HDAC 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 of (i) prostate cancer xenografts (PC-3) in nude mice and (ii) insitu prostate tumor in TRAMP mice. The following tasks were achieved: Aim 1: The radiosensitizing effects of VAD-18 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 and SAHA could sensitize PC-3 and DU-145 cells to radiation. Aim 2: Effects of VAD-18 and VAD-20 were mediated through cell cycle arrest, down-regulation of anti-apoptotic proteins, upregulation of pro-apoptotic proteins and abrogation of radiation-induced nuclear translocation of p65, thereby, enhancing cell death. Further, a novel transcription factor, USF-1 was identified which may be responsible for the radiosensitizing effects of these inhibitors. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA466149
Entities
People
- Mansoor M. Ahmed
- Seema Gupta