Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer.
Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer.
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DOI：
10.1007/s11605-015-3000-3
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Saluja AK
中科院分区：
文献类型：
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作者：
Modi S;Kir D;Giri B;Majumder K;Arora N;Dudeja V;Banerjee S;Saluja AK
奥沙利铂是 FOLFIRINOX 或 GEMOX/XELOX 方案中胰腺癌治疗的一部分。 DNA 损伤修复是导致这种癌症最终产生奥沙利铂耐药性的因素之一。临床前试验已证明雷公藤甲素/明内利德可有效对抗胰腺癌。在这项研究中，我们评估了雷公藤甲素和奥沙利铂联合治疗胰腺癌的疗效。使用奥沙利铂 (0-10μM)、低剂量雷公藤内酯醇 (50nM) 或两者的组合处理高度侵袭性胰腺癌细胞（MIA PaCa-2 和 PANC-1）24-48 小时。通过适当的方法评估细胞活力、细胞凋亡和DNA损伤。使用 qPCR 和蛋白质印迹对核苷酸切除修复途径成分进行定量。在胰腺癌原位小鼠模型中测试了低剂量明奈利特和奥沙利铂的组合。联合治疗显着抑制了胰腺癌细胞的增殖。雷公藤内酯醇可增强奥沙利铂诱导的细胞凋亡，并通过抑制奥沙利铂诱导的 DNA 损伤修复途径，使癌细胞对奥沙利铂诱导的 DNA 损伤敏感。低剂量的 Minnelide 和奥沙利铂的组合通过诱导这些肿瘤中显着的凋亡细胞死亡来抑制肿瘤进展。低剂量明奈利特和奥沙利铂的组合具有作为胰腺癌新治疗策略的巨大潜力。
Oxaliplatin is part of pancreatic cancer therapy in FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0-10μM), low dose triptolide (50nM) or a combination of both for 24-48h. Cell viability, apoptosis and DNA damage was evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin induced DNA damage by suppressing oxaliplatin induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as novel therapeutic strategy against pancreatic cancer.