期刊
INTERNATIONAL JOURNAL OF ONCOLOGY
卷 47, 期 1, 页码 262-268出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2015.3003
关键词
PARP inhibitors; AZD2281; BRCA mutation; allelic loss; breast cancer; autophagy; mitophagy; therapy
类别
PARP inhibitors are considered promising anticancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCAI or BRCA2 mutations and 9 different BRCA wild-type cell lines with BRCAI allelic loss. We found that AZD2281 was the most potent in the PARP inhibitors and induces significant growth inhibition (similar to 95%) in BRCAI mutant (HCC-1937, MDA-MB-436, and SUM-I49PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 treatment also resulted in growth inhibition ranging from 20 to 50% in cells with BRCAI allelic loss, including ER(+), HER2/Neu(+) and triple-negative breast cancer (TNBC) cells, but showed no effect in cells without with type BRCA without allelic loss. Knocking down of BRCAI or BRCA2 in TNBC cells with BRCAI allelic loss by RNA interference significantly enhanced AZD2281-induced growth inhibition and induced significant autophagy that was associated with mitophagy in cells with BRCA mutations. Inhibition of autophagy by gene knockdown significantly diminished AZD228 I-induced mitophagy and apoptosis, indicating that autophagic process mediates some of the downstream effects of PARP inhibitors. In conclusion, our data provide the first evidence of PARP inhibitor AZD2281 autophagy and mitophagy in breast cancer cell lines with BRCA mutations or BRCA-allelic loss. In addition, our results indicate that the patients with BRCA1 allelic loss may also benefit from PARP inhibitor therapy if BRCA is further inhibited.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据