The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione–thiazolidinone hybrid moleculesLes-6287,Les-6294, andLes-6328towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [3H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC50ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC50> 93.01 µM).Les-6287at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, whileLes-6294andLes-6328did that at 2.5 and 5 µM, respectively.Les-6287suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower.Les-6287induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells.Les-6287decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione–thiazolidinones might be promising agents for treating breast tumors of different types.
开发新型有效的乳腺癌治疗药物仍是肿瘤学领域的重点任务。该疾病的治疗策略在很大程度上取决于人乳腺癌细胞的基因型和表型。本研究旨在通过MTT法、克隆形成实验、[3H]-胸腺嘧啶掺入实验、流式细胞术、ELISA及qPCR技术，探究新型吡咯烷二酮-噻唑烷酮杂合分子Les-6287、Les-6294和Les-6328对不同类型人乳腺癌细胞系（MDA-MB-231、MCF-7、T-47D、HCC1954）及小鼠乳腺癌4T1细胞的抗肿瘤活性。实验显示，所研究的杂合分子对上述肿瘤细胞均具有毒性作用，其IC50值介于1.37至21.85 µM之间。同时，这些衍生物对人伪正常乳腺上皮细胞MCF-10A系表现出较低毒性（IC50 > 93.01 µM）。1 µM浓度的Les-6287可完全抑制MCF-7、MDA-MB-231和HCC1954细胞的集落形成，而Les-6294和Les-6328分别在2.5 µM和5 µM浓度下实现同等效果。Les-6287能显著抑制MCF-7、MDA-MB-231和HCC1954细胞的DNA生物合成，但对MCF-10A细胞的抑制作用明显较弱。该分子通过降低线粒体膜电位、增强caspase 3/7、8、9和10的活性，同时激活外源性及内源性凋亡途径，在所有免疫组化类型不同的人乳腺癌细胞中诱导细胞凋亡。此外，Les-6287能降低转移与侵袭相关蛋白MMP-2、MMP-9和ICAM-1的浓度，且未在处理的细胞中诱发自噬现象。综上所述，本研究结果表明合成的吡咯烷二酮-噻唑烷酮杂合分子有望成为治疗不同类型乳腺肿瘤的潜在候选药物。
肿瘤(癌症)患者之家