Xiao Ling-Yi, Kan Wai-Ming
aInstitute of Basic Medical Sciences, College of Medicine bDepartment of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Anticancer Drugs. 2017 Mar;28(3):316-321. doi: 10.1097/CAD.0000000000000467.
Cancer cells may acquire drug resistance by activating DNA repair signaling. Poly ADP-ribose polymerase (PARP) plays an important role in DNA repair and it is overexpressed in many cancers including chronic myeloid leukemia (CML). PARP inhibitors have been used either alone or with other drugs to augment cancer cell death. However, whether PARP inhibitors may also augment cell death induced by chemotherapeutic agents in CML cells has not been studied. K562 cells with or without PARP-1 knockdown were treated with cisplatin alone or together with olaparib. The cell death was investigated by propidium iodide staining and apoptosis-related proteins were detected by western blotting. Olaparib suppressed cisplatin-induced cell death in K562 and MEG01 cells. Moreover, PARP-1 knockdown also attenuated cisplatin toxicity in CML cells. Inhibition of PARP decreased cisplatin toxicity by attenuating caspase-3 and caspase-9 activity. These results indicated that the toxicity of cisplatin in CML cells requires PARP activity. Therefore, PARP inhibitors may not be useful with DNA-damaging agents such as cisplatin in CML treatment.
癌细胞可能通过激活DNA修复信号通路获得耐药性。聚ADP-核糖聚合酶（PARP）在DNA修复中起重要作用，且在包括慢性粒细胞白血病（CML）在内的许多癌症中过度表达。PARP抑制剂已被单独或与其他药物联合使用以增强癌细胞死亡。然而，PARP抑制剂是否也能增强化疗药物诱导的CML细胞死亡尚未得到研究。用顺铂单独或与奥拉帕尼联合处理有或没有PARP-1基因敲低的K562细胞。通过碘化丙啶染色研究细胞死亡情况，并通过蛋白质印迹法检测凋亡相关蛋白。奥拉帕尼抑制顺铂诱导的K562和MEG01细胞死亡。此外，PARP-1基因敲低也减弱了CML细胞中顺铂的毒性。抑制PARP通过减弱半胱天冬酶-3和半胱天冬酶-9的活性降低顺铂毒性。这些结果表明顺铂在CML细胞中的毒性需要PARP活性。因此，在CML治疗中，PARP抑制剂可能不适用于顺铂等DNA损伤剂。
