Mini Enrico, Landini Ida, Lucarini Laura, Lapucci Andrea, Napoli Cristina, Perrone Gabriele, Tassi Renato, Masini Emanuela, Moroni Flavio, Nobili Stefania
Oncol Res. 2017 Nov 2;25(9):1441-1451. doi: 10.3727/096504017X14926854178616. Epub 2017 Apr 20.
The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.
聚（ADP - 核糖）聚合酶（PARP）酶在细胞过程（如DNA损伤修复、基因组稳定性）的调节中起关键作用。已表明PARP抑制剂（PARPIs）对参与DNA修复机制（合成致死性）的基因功能失调的细胞具有选择性细胞毒性。药物诱导的PARP抑制增强了抗癌药物（如5 - 氟尿嘧啶）在增强DNA损伤方面的活性，其修复涉及PARP - 1活性。本研究的目的是评估新型PARPI HYDAMTIQ对具有不同DNA损伤反应途径特征（BRCA突变状态、微卫星状态和ATM表达水平）以及对5 - 氟尿嘧啶敏感/耐药程度的人肿瘤细胞系生长的抑制作用。与野生型细胞（C2 - 6、C2 - 12和C2 - 14 CAPAN - 1克隆以及MCF - 7）相比，HYDAMTIQ对BRCA2突变细胞系（CAPAN - 1）的细胞生长显示出更强的抑制作用。在HYDAMTIQ处理后，具有不同微卫星状态或不同MRE11突变状态的细胞之间未观察到统计学上的显著差异。与高表达ATM的H630细胞相比，HYDAMTIQ在低表达ATM的SW620细胞中诱导出更大的抗增殖作用。最后，HYDAMTIQ和5 - 氟尿嘧啶的联合使用对SW620细胞生长的抑制具有协同作用，而对H630细胞生长具有拮抗作用。我们的结果表明，新型PARP抑制剂HYDAMTIQ能有效抑制具有缺陷DNA损伤反应途径的人肿瘤细胞生长，并与5 - 氟尿嘧啶联合发挥协同细胞毒性作用。这些数据提供了合成致死性的相关实例，并为这种新型PARPI的进一步开发提供了证据。
