T. Minami, M. Adachi, Rina Kawamura
Jul 15, 2005
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Journal
Clinical Cancer Research
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. 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. 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 α-tocopherol, but were much less sensitive to a p38 inhibitor SB203580. 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.