Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity
Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity
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DOI：
10.1158/1078-0432.ccr-05-0085
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发表时间：
2005-07-15
影响因子：
11.5
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Minami, T;Adachi, M;Imai, K
目的：非甾体类药物舒林酸是一种很有前途的结肠癌化学预防剂，在此，我们讨论舒林酸是否增强蛋白酶体抑制剂硼替佐米（PS-341）在结肠癌cells.Experimental Design中的抗癌作用：通过细胞死亡，集落形成试验，DNA片段化和DLD-1异种移植瘤的肿瘤进展来评估舒林酸与硼替佐米的协同作用。使用羧基-H（2）DCFDA或二氢乙锭检测活性氧（ROS）的产生。通过血红素加氧酶-1诱导和应激激活的丝裂原活化蛋白激酶p38和c-Jun-NH 2-激酶磷酸化来评估氧化应激。结果：舒林酸及其代谢产物可增强硼替佐米对DLD-1和BM 314结肠癌细胞的抗肿瘤作用。舒林酸诱导ROS产生并增强硼替佐米介导的氧化应激和随后的DNA损伤。结论：舒林克通过协同ROS生成和DNA氧化损伤增强硼替佐米的抗结肠癌作用，是一种新型的联合治疗结肠癌的药物。
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 sulinclac 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-H(2)DCFDA 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 a-tocopherol, but were much less sensitive to a p38 inhibitor SB203580.Conclusion: Sulinclac 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.