Cationic liposome codelivering PI3K pathway regulator improves the response of BRCA1-deficient breast cancer cells to PARP1 inhibition
Cationic liposome codelivering PI3K pathway regulator improves the response of BRCA1-deficient breast cancer cells to PARP1 inhibition
复制标题
阳离子脂质体共传递 PI3K 通路调节剂改善 BRCA1 缺陷乳腺癌细胞对 PARP1 抑制的反应
DOI：
10.1002/jcb.28574
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发表时间：
2019
影响因子：
4
通讯作者：
Wang Xiaozhen
中科院分区：
文献类型：
--
作者：
Zhang Haipeng;Yu Na;Chen Yan;Yan Kaowen;Wang Xiaozhen
尽管乳腺癌治疗取得了一些进展，但BRCA 1缺陷型乳腺癌的有效治疗仍是一个巨大的挑战。已经证明，PI 3 K通路在BRCA 1缺陷型乳腺癌中被不适当地激活，这可以被microRNA 451（miR-451）下调。此外，尽管PARP 1抑制剂在临床前和临床研究中显示出相对积极的结果，但需要进一步努力降低耐药性以及降低全身毒性。为此，通过将miR-451模拟物和PARP 1抑制剂包封在同一阳离子脂质体中，我们研究了通过调节PI 3 K途径增强PARP 1抑制对BRCA 1缺陷型乳腺癌的反应的潜力。我们的研究结果表明，在BRCA 1缺陷的人乳腺癌细胞系中，PARP 1抑制导致DNA损伤，活力降低，G2/M期阻滞以及凋亡。相反，单一的PI 3 K抑制诱导G1期阻滞沿着延迟的细胞增殖。然而，值得注意的是，与单独PARP抑制相比，PARP抑制剂和PI 3 K调节剂的组合可以发挥协同作用，从而明显降低细胞增殖，这也通过使用异种移植肿瘤模型的体内抗肿瘤测定得到证实。总的来说，我们的研究结果为BRCA 1缺陷型人类乳腺癌的治疗提供了一种替代但上级的策略，可能有利于临床应用。
Although some progresses have been made in breast cancer therapy, effective treatment for BRCA1‐deficient breast cancer remains to be a great challenge. It has been demonstrated that the PI3K pathway is inappropriately activated in BRCA1‐deficient breast cancers which can be downregulated by microRNA 451 (miR‐451). In addition, although PARP1 inhibitors showed relatively positive results in both preclinical and clinical studies, additional efforts to decrease drug resistance as well as reduce systematic toxicity need to be addressed. To this end, by encapsulating the miR‐451 mimic and PARP1 inhibitor in the same cationic liposome, we examined the potential of enhancing the response of PARP1 inhibition on BRCA1‐deficient breast cancer by regulating the PI3K pathway. Our results revealed that in BRCA1‐deficient human breast cancer cell line, PARP1 inhibition resulted in DNA damage with viability decrease, G2/M arrest as well as apoptosis. In contrast, single PI3K inhibition induced G1 arrest along with retarded cell proliferation. However, it was noted that combination of PARP inhibitor and PI3K regulator could exert synergetic function to evidently decrease cell proliferation compared with PARP inhibition alone, which was also confirmed by in vivo antitumor assay using xenograft tumor models. Collectively, our results offer an alternative but superior strategy for the therapy of BRCA1‐deficient human breast cancers which may benefit the clinical applications.