Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors (PARPi) leads to a limited objective response rate in cervical cancer patients with homologous recombination (HR) repair-deficiency, urgently requiring more studies to improve the therapeutic efficacy of PARPi during cervical cancer progression. In the study, we attempted to explore the effects of co-treatments with PARPi rucaparib phosphate (Ruc-P) and PI3Kα inhibitor CNX-1351 on cervical cancer growth in vivo and in vitro. Our results showed that CNX-1351 significantly facilitated the anti-cancer role of Ruc-P in cervical cancer, as proved by the remarkably decreased cell proliferation. In addition, G2/M cell cycle arrest and apoptosis were considerably induced by CNX-1351 and Ruc-P combinational treatments compared with the drug alone-treated group. Furthermore, the capacity of Ruc-P to trigger DNA damage was dramatically promoted in cervical cancer cells co-treated with CNX-1351 and Ruc-P, accompanied with elevated expression of γ-H2AX. Importantly, we found that Ruc-P markedly down-regulated the expression of HR markers, including breast cancer 1/2 (BRCA1/2) and RAD51, along with evidently decreased HR repair efficacy, which was, notably, further promoted in cervical cancer cells co-incubated with CNX-1351. Consistently, our in vivo findings confirmed that CNX-1351 administration markedly improved the function of Ruc-P via co-treatments to reduce tumor growth in a xenograft mouse model with cervical cancer. Together, all these results provided new insights into the combinational blockage of PARP and PI3K signals on the suppression of cervical cancer, which was more efficient than either drug alone, and thus could be considered as a promising therapeutic strategy in future.

聚ADP-核糖聚合酶（PARP）抑制剂（PARPi）单药治疗导致同源重组（HR）修复缺陷的宫颈癌患者客观缓解率有限，迫切需要更多的研究来提高PARPi在宫颈癌进展过程中的治疗效果. 在这项研究中，我们试图在体内和体外探索与 PARPi rucaparib 磷酸盐 (Ruc-P) 和 PI3Kα 抑制剂 CNX-1351 共同治疗对宫颈癌生长的影响. 我们的结果表明，CNX-1351 显着促进了 Ruc-P 在宫颈癌中的抗癌作用，这由显着降低的细胞增殖证明。此外，与单独药物治疗组相比，CNX-1351 和 Ruc-P 联合治疗显着诱导 G2/M 细胞周期停滞和细胞凋亡。此外，在与 CNX-1351 和 Ruc-P 共同处理的宫颈癌细胞中，Ruc-P 触发 DNA 损伤的能力显着提高，伴随着 γ-H2AX 的表达升高。重要的是，我们发现 Ruc-P 显着下调 HR 标志物的表达，包括乳腺癌 1/2 (BRCA1/2) 和 RAD51，同时明显降低 HR 修复功效，尤其是在宫颈癌中得到进一步促进细胞与 CNX-1351 共孵育。始终如一地，我们的体内研究结果证实，在宫颈癌异种移植小鼠模型中，CNX-1351 的给药显着改善了 Ruc-P 的功能，以减少肿瘤生长。总之，所有这些结果为联合阻断 PARP 和 PI3K 信号对宫颈癌的抑制提供了新的见解，这比单独使用任何一种药物更有效，因此可以被视为未来有前景的治疗策略。