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首页> 外文期刊>RSC Advances >Novel PARP inhibitors sensitize human leukemic cells in an endogenous PARP activity dependent manner
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Novel PARP inhibitors sensitize human leukemic cells in an endogenous PARP activity dependent manner

机译：新型PARP抑制剂以内源性PARP活性依赖性方式敏化人白血病细胞

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Poly(ADP-ribose) polymerase (PARP) is a critical nuclear enzyme which safeguards genome stability from genotoxic insults and helps in DNA repair. Inhibition of PARP results in sustained DNA damage in cancer cells. PARP inhibitors are known to play an important role in chemotherapy as single agents in many DNA repair pathway deficient tumor cells or in combination with several other chemotherapeutic agents. In the present study, we synthesize and characterize novel pyridazine derivatives, and evaluate their potential for use as PARP inhibitors. Results show that pyridazine derivatives inhibited the PARP1 enzymatic activity at the nanomolar range and showed anti-proliferative activity in leukemic cells. Interestingly, human leukemic cell line, Nalm6, in which PARP1 and PARP2 expression as well as intrinsic PARP activity are high, showed significant sensitivity for the novel inhibitors compared to other leukemic cells. Among the inhibitors, P10 showed maximum inhibition of intrinsic PARP activity and inhibited cell proliferation in Nalm6 cells. Besides P10 also showed maximum inhibition against purified PARP1 protein, which was comparable to olaparib in our assays. Newly synthesized compounds also showed remarkable DNA trapping ability, which is a signature feature of many PARP inhibitors. Importantly, P10 also induced late S and G2/M arrest in Nalm6 cells, indicating accumulation of DNA damage. Therefore, we identify P10 as a potential PARP inhibitor, which can be developed as a chemotherapeutic agent.
机译：聚（ADP-核糖）聚合酶（PARP）是一种临界核酶，其保护基因毒性损伤的基因组稳定性，并有助于DNA修复。对PARP的抑制导致癌细胞中持续的DNA损伤。已知PARP抑制剂在化疗中发挥重要作用，作为许多DNA修复途径缺乏肿瘤细胞或与几种其他化学治疗剂组合的单一药剂。在本研究中，我们合成并表征新的哒嗪衍生物，并评估它们用作PARP抑制剂的可能性。结果表明，吡啶嗪衍生物在纳米摩尔范围内抑制PARP1酶活性，并在白血病细胞中显示出抗增殖活性。有趣的是，人的白血病细胞系NALM6，其中PARP1和PARP2表达以及内在PARP活性很高，与其他白血病细胞相比，新型抑制剂的显着灵敏度。在抑制剂中，P10显示出最大限度地抑制内在PARP活性和抑制NALM6细胞中细胞增殖。除了P10还表现出对纯化PARP1蛋白的最大抑制，其与我们的测定中的奥拉帕布相当。新合成的化合物还显示出显着的DNA捕获能力，这是许多PARP抑制剂的特征。重要的是，P10还诱导在NALM6细胞中诱导的S和G2 / M停滞，表明DNA损伤的积累。因此，我们将P10鉴定为潜在的PARP抑制剂，其可以作为化学治疗剂开发。

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