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 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 of(i) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2005
- Accession Number
- ADA446334
Entities
People
- Mansoor M. Ahmed
- Seema Gupta
Organizations
- University of Kentucky