Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Beirut, Lebanon.
Laboratory for Medicinal Chemistry and Natural Products, Faculty of Sciences-I and PRASE-EDST, Lebanese University, Hadath, Beirut, Lebanon.
Genes Genomics. 2019 Dec;41(12):1431-1443. doi: 10.1007/s13258-019-00866-y. Epub 2019 Sep 20.
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.
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.
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.
Collectively, our results demonstrate an anti-TNBC activity of Cisplatin + thiosemicarbazone compound 4 combination mediated via induction of apoptosis.
乳腺癌是女性最常见的恶性肿瘤，也是全球癌症相关死亡的主要原因。三阴性乳腺癌（TNBC）缺乏雌激素、孕激素和 HER2 受体的表达，具有侵袭性的临床表型，对化疗敏感，但对激素或靶向免疫治疗不敏感。为了寻找有效的 TNBC 治疗药物，我们对一组硫代缩氨基脲衍生物进行了筛选，以评估其对 MDA-MB-231 乳腺癌细胞系的细胞毒性作用。
采用 MTT 法检测细胞活力。Western blot 检测 p53 磷酸化状态、聚（ADP-核糖）聚合酶（PARP）切割以及 Bcl2 和 Bax 蛋白水平。采用实时定量 PCR 检测 miRNA 表达水平。
顺铂+硫代缩氨基脲化合物 4 联合用药具有显著的抗 TNBC 作用。顺铂+化合物 4 可显著增强 p53 磷酸化，诱导 Bax 蛋白表达增加，降低 Bcl2 蛋白水平，增强 PARP 切割，并调节 TNBCs 中 miRNA 表达谱，其中 miR-125a-5p 和 miR-181a-5p 的表达明显上调。有趣的是，miR-125a-5p 和 miR-181a-5p 可以通过结合其 3'UTR 中的靶位点显著下调 BCL2 表达。
综上所述，我们的研究结果表明，顺铂+硫代缩氨基脲化合物 4 联合用药具有抗 TNBC 活性，其作用机制可能与诱导细胞凋亡有关。
