Richardson D S, Allen P D, Kelsey S M, Newland A C
Department of Haematology, St. Bartholomew's and Royal London School of Medicine, United Kingdom.
Adv Exp Med Biol. 1999;457:267-79. doi: 10.1007/978-1-4615-4811-9_29.
Poly (ADP-ribose) polymerase (PARP) is activated following binding to DNA strand breaks and is cleaved in cells undergoing apoptosis. Work predominantly in murine systems has suggested that inhibitors of PARP might potentiate the effects of chemotherapeutic agents and be used as adjuncts to cancer therapy. Therefore, we studied the role of PARP in drug-induced apoptosis in HL-60, myeloid leukaemia cells and found that pre-treatment with 3-aminobenzamide (3AB) or 6(5H)-phenanthridinone, inhibitors of PARP, resulted in resistance to, rather than potentiation of apoptotic death induced by DNA-damaging agents, idarubicin, etoposide and fludarabine, as determined by flow cytometry, following propidium iodide staining. 3AB treated CEM/VLB100, mdr-expressing human lymphoblastic leukaemia cells were also found to be more resistant to idarubicin compared to cells treated with idarubicin alone, however, apoptosis was not reduced in parental CCRF-CEM cells under the same conditions. Similar results were obtained using agents with primary modes of action which do not involve DNA damage, vinblastine and a fas-ligating antibody (CH11). The precise role of PARP has yet to be defined but might involve effects on cell cycle progression. We conclude that PARP activation appears to be involved in apoptosis in certain leukaemic cell lines and that these effects are independent of lineage or p-glycoprotein. Constitutive failure to activate PARP might be responsible for conferring resistance to apoptosis.
聚（ADP - 核糖）聚合酶（PARP）在与DNA链断裂结合后被激活，并在经历凋亡的细胞中被切割。主要在小鼠系统中的研究表明，PARP抑制剂可能增强化疗药物的效果，并可用作癌症治疗的辅助药物。因此，我们研究了PARP在HL - 60髓系白血病细胞药物诱导凋亡中的作用，发现用PARP抑制剂3 - 氨基苯甲酰胺（3AB）或6（5H） - 菲啶酮预处理后，细胞对DNA损伤剂伊达比星、依托泊苷和氟达拉滨诱导的凋亡死亡产生抗性，而非增强作用，这是通过碘化丙啶染色后流式细胞术测定的。还发现，与单独用伊达比星处理的细胞相比，3AB处理的表达多药耐药（mdr）的人淋巴细胞白血病细胞CEM/VLB100对伊达比星更具抗性，然而，在相同条件下，亲代CCRF - CEM细胞的凋亡并未减少。使用主要作用方式不涉及DNA损伤的药物长春碱和一种fas连接抗体（CH11）也获得了类似结果。PARP的确切作用尚待确定，但可能涉及对细胞周期进程的影响。我们得出结论，PARP激活似乎参与某些白血病细胞系的凋亡，且这些作用与细胞谱系或P - 糖蛋白无关。PARP激活的持续性失败可能是导致细胞对凋亡产生抗性的原因。
