Beberok Artur, Rzepka Zuzanna, Rok Jakub, Karkoszka-Stanowska Marta, Wrześniok Dorota
Faculty of Pharmaceutical Sciences in Sosnowiec, Department of Pharmaceutical Chemistry, Medical University of Silesia, Jagiellońska 4, Sosnowiec, 41-200, Poland.
Pharmacol Rep. 2025 Sep 2. doi: 10.1007/s43440-025-00780-z.
Triple-negative breast cancer (TNBC) is characterized by high invasiveness, high metastatic potential, and poor prognosis. TNBC is not sensitive to endocrine therapy or HER2-targeted treatment, highlighting the need for the development of standardized TNBC treatment regimens. Thus, the development of new TNBC treatment strategies has become an urgent need. MIM1 - BH3 mimetic, which inhibits Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MOXI) can modulate the Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of MIM1 and MOXI/MIM1 mixtures on the viability and apoptosis in MDA-MB-231 breast cancer cells.
The viability of cells was assessed by the WST-1 assay. The proapoptotic activity of the tested compounds was determined by cytometric technique.
The results showed that MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of MOXI and MIM1 mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity - shown as a modulatory effect on mitochondrial membrane potential, cell cycle distribution, or DNA fragmentation, toward MDA-MB-231 cells when compared with MIM1 or MOXI alone.
We have reported, for the first time, the high proapoptotic activity of MIM1 toward MDA-MB-231 cells pointing to the Mcl-1 protein as an important molecular target. Moreover, the observed potential synergistic mode of action (expressed as a significant enhancement of the induction of apoptosis process) detected for MOXI and MIM1 in the two-component model may provide a new direction for further in vitro and in vivo experiments concerning the role of Mcl-1 protein in the treatment of TNBC.
Not applicable.
三阴性乳腺癌（TNBC）具有高侵袭性、高转移潜能和预后不良的特点。TNBC对内分泌治疗或HER2靶向治疗不敏感，这凸显了制定标准化TNBC治疗方案的必要性。因此，开发新的TNBC治疗策略已成为迫切需求。MIM1 - BH3模拟物可抑制Mcl-1抗凋亡蛋白，可能是一种能够诱导细胞凋亡的有效分子。此前，我们发现莫西沙星（MOXI）可调节Mcl-1蛋白表达。因此，在本研究中，我们评估了MIM1以及MOXI/MIM1混合物对MDA-MB-231乳腺癌细胞活力和凋亡的影响。
通过WST-1法评估细胞活力。采用细胞计数技术测定受试化合物的促凋亡活性。
结果表明，MIM1具有高细胞毒性和促凋亡潜能。在二元模型中，我们证明与单独使用MIM1或MOXI相比，使用MOXI和MIM1混合物可显著增强对MDA-MB-231细胞的细胞毒性和促凋亡活性，表现为对线粒体膜电位、细胞周期分布或DNA片段化的调节作用。
我们首次报道了MIM1对MDA-MB-231细胞具有高促凋亡活性，表明Mcl-1蛋白是一个重要的分子靶点。此外，在二元模型中观察到的MOXI和MIM1的潜在协同作用模式（表现为凋亡诱导过程的显著增强）可能为进一步开展关于Mcl-1蛋白在TNBC治疗中作用的体外和体内实验提供新方向。
不适用。
