Nair Rakesh Sathish, Kumar Jerald Mahesh, Jose Jedy, Somasundaram Veena, Hemalatha Sreelatha K, Sengodan Satheesh Kumar, Nadhan Revathy, Anilkumar Thapasimuthu V, Srinivas Priya
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
Centre for Cellular and Molecular Biology, Hyderabad, India.
Sci Rep. 2016 May 25;6:26631. doi: 10.1038/srep26631.
We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1(Co/Co) and WAP-Cre; BRCA1(Co/Co), at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defective triple negative BRCA1 mutant cell lines and in mouse models occur by inducing ROS mediated DNA DSB. The toxicity profile as compared with CN in transgenic mice provides evidence for PB's safer disposition as a therapeutic lead in breast cancer drug development.
我们之前已经表明，白花丹醌（PB）可对BRCA1缺陷型卵巢癌细胞诱导选择性细胞毒性；然而，该分子在BRCA1突变型乳腺癌中的作用尚未进行分析。在此，我们报告PB诱导的活性氧（ROS）导致DNA双链断裂（DSB），并通过ATR/ATM激酶激活下游信号传导及随后的细胞凋亡。PB降低BRCA1缺陷型乳腺癌细胞中DNA依赖性蛋白激酶（DNA-PK）的表达并抑制非同源末端连接（NHEJ）活性。此外，PB在两种不同的BRCA1条件性敲除小鼠模型：MMTV-Cre；BRCA1（Co/Co）和WAP-Cre；BRCA1（Co/Co）中，以2mg/kg体重诱导细胞凋亡，但需要32mg/kg的卡铂（CN）才能在其中诱导细胞凋亡。这是首次使用两种不同组织特异性启动子驱动的、带有BRCA1第11外显子缺失的转基因小鼠模型进行临床前药物测试的研究。PB在同源重组（HR）缺陷型三阴性BRCA1突变细胞系和小鼠模型中诱导的细胞凋亡是通过诱导ROS介导的DNA DSB发生的。与转基因小鼠中的CN相比，其毒性特征为PB作为乳腺癌药物开发中的治疗先导提供了更安全处置的证据。
