Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Department of NEUROFARBA, University of Florence, Florence, Italy.
Oncol Res. 2018 Mar 5;26(2):333-334. doi: 10.3727/096504018X15187172557369.
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）在细胞过程的调节中发挥关键作用（例如，DNA 损伤修复，基因组稳定性）。已经表明，PARP 抑制剂（PARPIs）对涉及 DNA 修复机制（合成致死性）中基因功能障碍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的活性，如氟尿嘧啶，增强了 DNA 损伤，其修复涉及 PARP-1 活性。本研究的目的是评估新型 PARPI HYDAMTIQ 对具有不同特征的人肿瘤细胞系生长的抑制作用，这些特征涉及 DNA 损伤反应途径（BRCA 突变状态、微卫星状态和 ATM 表达水平）以及对氟尿嘧啶的敏感性/耐药性程度。与野生型细胞（C2-6、C2-12 和 C2-14 CAPAN-1 克隆和 MCF-7）相比，HYDAMTIQ 对 BRCA2 突变细胞系（CAPAN-1）中的细胞生长具有更强的抑制作用。在暴露于 HYDAMTIQ 后，具有不同 MS 状态或不同 MRE11 突变状态的细胞之间没有观察到统计学上的显着差异。在表达低水平 ATM 的 SW620 细胞中，HYDAMTIQ 诱导的抗增殖作用大于表达高水平 ATM 的 H630 细胞。最后，HYDAMTIQ 与氟尿嘧啶的联合对 SW620 细胞生长的抑制具有协同作用，对 H630 细胞生长的抑制具有拮抗作用。我们的结果表明，新型 PARP 抑制剂 HYDAMTIQ 能够强烈抑制具有缺陷 DNA 损伤反应途径的人肿瘤细胞的生长，并与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示例，并为进一步开发这种新型 PARPI 提供了证据。
