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Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2005 Jul 15; Vol. 11 (14), pp. 5248-56. - Publication Year :
- 2005
-
Abstract
- Purpose: The nonsteroidal antiinflammatory drug sulindac is a promising chemopreventive agent against colon cancer. Here, we address whether sulindac enhances the anticancer effects of the proteasome inhibitor bortezomib (PS-341) in colon cancer cells.<br />Experimental Design: The synergistic effects of sulindac with bortezomib were evaluated by cell death, colony formation assay, DNA fragmentation, and tumor progression of DLD-1 xenografts. Reactive oxygen species (ROS) generation was detected using carboxy-H2DCFDA or dihydroethidium. Oxidative stress was evaluated by heme oxygenase-1 induction and stress-activated mitogen-activated protein kinases p38 and c-Jun-NH2-kinase phosphorylation. Oxidative DNA damage was evaluated by histone H2AX phosphorylation and accumulation of 8-hydroxy-2'-deoxyguanosine.<br />Results: Sulindac and its metabolites enhanced the anticancer effects of bortezomib in DLD-1 and BM314 colon cancer cells. Sulindac induced ROS generation and enhanced bortezomib-mediated oxidative stress and subsequent DNA damage. Their combined effects were highly sensitive to free radical scavengers L-N-acetylcysteine and alpha-tocopherol, but were much less sensitive to a p38 inhibitor SB203580.<br />Conclusion: Sulindac synergistically augments the anticancer effects of bortezomib primarily through cooperative ROS generation and oxidative DNA damage, thereby representing a novel combination therapy against colon cancer.
- Subjects :
- Animals
Bortezomib
Cell Death
Disease Progression
Drug Interactions
Humans
Mice
Mice, Nude
Transplantation, Heterologous
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Antineoplastic Agents pharmacology
Boronic Acids pharmacology
Colonic Neoplasms pathology
DNA Damage
Oxidative Stress drug effects
Pyrazines pharmacology
Reactive Oxygen Species
Sulindac pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 11
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 16033843
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-05-0085