Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cδ
Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cδ
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DOI：
10.1074/jbc.m100385200
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发表时间：
2002-01-25
影响因子：
4.8
通讯作者：
Freund, GG
中科院分区：
文献类型：
--
作者：
Godbout, JP;Pesavento, J;Freund, GG
抗肿瘤药物的细胞毒性副作用在1型或2型糖尿病患者中增加，其机制尚不清楚。我们报告说，循环葡萄糖代谢物，冰毒。丙酮醛（MGO）通过激活蛋白激酶C δ（PKC δ）增强顺铂诱导的细胞凋亡。我们发现用抗氧化剂N-乙酰半胱氨酸处理骨髓瘤细胞完全阻断了顺铂依赖的细胞内GSH氧化、活性氧（ROS）生成、聚（ADP-核糖）聚合酶裂解和细胞凋亡。重要的是，用反应性羰基MGO和顺铂共处理细胞使细胞凋亡增加了90%，超过了组合MGO和顺铂处理的预期累加效应。当检查ROS产生时，也观察到这种相同的协同作用。MGO和顺铂使PKC δ活性增加4倍，这种作用被PKC δ抑制剂rottlerin阻断，但不被NAC阻断。此外，rottlerin阻断MGO和顺铂联合诱导的ROS产生和细胞凋亡。最后，MGO和顺铂诱导c-Abl活化和c-Abl：PKC δ结合。Rottlerin阻断c-Abl活化，但c-Abl抑制剂STI-571使MGO和顺铂诱导的细胞凋亡增加50%。总之，这些数据表明，MGO协同增强顺铂诱导的细胞凋亡，通过激活PKC δ和PKC δ是至关重要的细胞死亡和细胞存活途径。这些发现表明，在糖尿病患者中，氧化应激增强可增强诱导DNA损伤的药物的细胞毒性。
The cytotoxic side effects of anti-neoplastic drugs are increased in patients with either type 1 or type 2 diabetes mellitus by a mechanism that is not clearly defined. We report that the circulating glucose metabolite, meth. ylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). We found that treatment of myeloma cells with the antioxidant N-acetylcysteine completely blocked cisplatin-dependent intracellular GSH oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Importantly, co-treatment of cells with the reactive carbonyl MGO and cisplatin increased apoptosis by 90% over the expected additive effect of combined MGO and cisplatin treatment. This same synergism was also observed when ROS generation was examined. MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC. Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis. Finally, MGO and cisplatin induced c-Abl activation and c-Abl:PKCdelta association. Rottlerin blocked c-Abl activation, but the c-Abl inhibitor STI-571 increased MGO and cisplatin-induced apoptosis by 50%,. Taken together these data indicate that MGO synergistically enhances cisplatin-induced apoptosis through activation of PKCdelta and that PKCdelta is critical to both cell death and cell survival pathways. These findings suggest that in the patient with diabetes mellitus heightened oxidative stress can enhance the cytotoxicity of agents that induce DNA damage.