Cell Cycle Dependence of TRIAL Sensitivity in Prostate Cancer Cells
Abstract
The proteasome inhibitor bortezomib (PS-341, Velcade) synergizes with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) acts via a p21- dependent mechanism to induce high levels of apoptosis in prostate cancer cells. Our further investigation into the molecular mechanisms underlying the effects of bortezomib implicated endoplasmic reticular (ER) stress in its anti-tumoral effects. These effects also provide us with a molecular mechanism to explain the observed anti-angiogenic effects of bortezomib in prostate cancer cells. We have generated luciferase-transduced variants of our human prostate cancer cell lines in order to use them to generate orthotopic tumors in nude mice that can be imaged non-invasively. We plan to use these models in the coming 6-12 months to test the toxicity and anti-tumoral efficacy of combination therapy with bortezomib plus anti-DR5 antibodies in vivo. Preliminary toxicity studies confirmed that mice tolerate daily therapy with recombinant TRAIL plus biweekly therapy with bortezomib (at its MTD) very well.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2007
- Accession Number
- ADA481900
Entities
People
- David J. Mcconkey
Organizations
- The University of Texas MD Anderson Cancer Center