BACKGROUND Breast cancer, the most commonly diagnosed malignancy in women, accounts for the highest cancer-related deaths worldwide. Triple negative breast cancer (TNBC), lacking the expression of estrogen, progesterone and HER2 receptors, has an aggressive clinical phenotype and is susceptible to chemotherapy but not to hormonal or targeted immunotherapy. In an attempt to identify potent and selective anti-TNBC agents, a set of thiosemicarbazone derivatives were screened for their cytotoxic activity against MDA-MB 231 breast cancer cell line. METHODS MTT assay was used to examine cell viability. P53 phosphorylation status, poly (ADP-ribose) polymerase (PARP) cleavage as well as Bcl2 and Bax protein levels were assessed by Western blot. Quantitative Real Time-PCR was carried out to characterize miRNAs expression levels. RESULTS Combining Cisplatin + thiosemicarbazone compound 4 showed potent anti-TNBC potential. Cisplatin + compound 4 significantly enhanced p53 phosphorylation, induced Bax amount, reduced Bcl2 protein levels, enhanced PARP cleavage and modulated miRNAs expression profile in TNBCs, with a particular overexpression of miR-125a-5p and miR-181a-5p. Intriguingly, miR-125a-5p and miR-181a-5p could significantly downregulate BCL2 expression by binding to their target sites in the 3'UTR. CONCLUSIONS Collectively, our results demonstrate an anti-TNBC activity of Cisplatin + thiosemicarbazone compound 4 combination mediated via induction of apoptosis.

中文翻译：

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硫半脲衍生物诱导三阴性乳腺癌细胞凋亡：miRNA-125a-5p和miRNA-181a-5p的可能作用。

背景技术乳腺癌是女性中最常被诊断出的恶性肿瘤，在全球范围内与癌症相关的死亡人数最高。三阴性乳腺癌（TNBC）缺乏雌激素，孕激素和HER2受体的表达，具有侵略性的临床表型，易受化学疗法的影响，但对激素或靶向免疫疗法不敏感。为了鉴定有效和选择性的抗TNBC剂，针对硫代半碳酰胺衍生物对MDA-MB 231乳腺癌细胞系的细胞毒活性进行了筛选。方法采用MTT法检测细胞活力。通过蛋白质印迹评估P53磷酸化状态，聚（ADP-核糖）聚合酶（PARP）裂解以及Bcl2和Bax蛋白水平。进行实时定量PCR以表征miRNA的表达水平。结果顺铂+硫半脲化合物4的组合显示出有效的抗TNBC潜力。顺铂+化合物4显着增强了TNBC中的p53磷酸化，诱导的Bax量，降低的Bcl2蛋白水平，增强的PARP裂解和调节的miRNA表达谱，特别是miR-125a-5p和miR-181a-5p的过表达。有趣的是，miR-125a-5p和miR-181a-5p可以通过与3'UTR中的靶位点结合来显着下调BCL2表达。结论我们的研究结果表明，通过诱导细胞凋亡介导的顺铂+硫代半脲化合物4组合具有抗TNBC活性。增强了TNBC中的PARP裂解和调节的miRNA表达谱，特别是miR-125a-5p和miR-181a-5p的过表达。有趣的是，miR-125a-5p和miR-181a-5p可以通过与3'UTR中的靶位点结合来显着下调BCL2表达。结论我们的研究结果表明，通过诱导细胞凋亡介导的顺铂+硫代半脲化合物4组合具有抗TNBC活性。增强了TNBC中的PARP裂解和调节的miRNA表达谱，特别是miR-125a-5p和miR-181a-5p的过表达。有趣的是，miR-125a-5p和miR-181a-5p可以通过与3'UTR中的靶位点结合来显着下调BCL2表达。结论我们的研究结果表明，通过诱导细胞凋亡介导的顺铂+硫代半脲化合物4组合具有抗TNBC活性。