In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

译文

:在这项研究中,我们评估了新型八氢吡嗪[2,1-a:5,4-a']二异喹啉衍生物(1-7)在MCF-7和MDA-MB-231乳腺癌细胞中的细胞毒活性和抗增殖能力线。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。在与被测化合物孵育24小时后,测定了胱天蛋白酶3、8、9和10的活性,以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行比较。我们的研究表明,在两种分析过的乳腺癌细胞系中,活性最高的化合物是化合物3和4。我们还观察到所有化合物均可诱导细胞凋亡。我们证明了胱天蛋白酶3,8,9和10较高的活动,这证实凋亡的诱导与外部和内部细胞死亡途径相关。我们的研究表明,通过激活外在和内在的凋亡途径,二异喹啉衍生物类中的新化合物有望成为抗癌治疗的候选药物。

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