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Sulindac Enhances the Proteasome Inhibitor Bortezomib-Mediated Oxidative Stress and Anticancer Activity

Authors' Affiliations: ¹ First Department of Internal Medicine and ² Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Japan

Requests for reprints: Masaaki Adachi, The First Department of Internal Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo 060-8543, Japan. Phone: 81-11-611-2111; Fax: 81-11-611-2282; E-mail: adachi{at}sapmed.ac.jp.

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 -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.

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