There is a need to improve and extend the use of clinically approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallointercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARPi olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a >300-fold increase in olaparib potency in TNBC, the largest nongenetic PARPi enhancement effect described to date. A negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP-activated pChk1 signaling are consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis, and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallointercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC.

中文翻译：

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Metallointercalator [Ru(dppz)2(PIP)]2+ 使 BRCA 野生型三阴性乳腺癌细胞对 PARP 抑制过敏。

需要改进和扩大临床批准的聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂 (PARPi) 的使用，包括用于 BRCA 野生型三阴性乳腺癌 (TNBC)。钌 (II) 多吡啶基复合物 (RPC) 金属嵌入剂可以迅速阻止 DNA 复制叉进程的证明为它们与 DNA 损伤反应 (DDR) 抑制剂组合以在癌细胞中实现协同作用提供了基本原理。本研究的目的是评估多嵌入剂 [Ru(dppz)2(PIP)]2+ (dppz = 双吡啶并[3,2-a:2',3'-c]吩嗪, PIP = (2-(苯基)咪唑[4,5-f][1,10]菲咯啉，Ru-PIP) 与 PARPi olaparib 和 NU1025 并列。细胞增殖和克隆存活测定表明，在 MDA-MB-231 TNBC 和 MCF7 人乳腺癌细胞中，Ru-PIP 和奥拉帕尼之间存在协同关系。引人注目的是，低剂量 Ru-PIP 使两种细胞系都对奥拉帕尼过敏，奥拉帕尼在 TNBC 中的效力增加了 300 倍以上，这是迄今为止描述的最大的非遗传 PARPi 增强作用。对于任何测试的组合，观察到对正常人成纤维细胞活力的影响可以忽略不计。增加的 DNA 双链断裂 (DSB) 损伤水平和 olaparib 消除 Ru-PIP 激活的 pChk1 信号传导与 PARPi 促进的 Ru-PIP 相关的停滞复制叉崩溃一致。与单药条件相比，这导致联合治疗的 G2/M 细胞周期停滞、细胞凋亡和细胞运动性降低。