Gornowicz Agnieszka, Pawłowska Natalia, Czajkowska Anna, Czarnomysy Robert, Bielawska Anna, Bielawski Krzysztof, Michalak Olga, Staszewska-Krajewska Olga, Kałuża Zbigniew
1 Department of Biotechnology, Medical University of Bialystok, Bialystok, Poland.
2 Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Bialystok, Poland.
Tumour Biol. 2017 Jun;39(6):1010428317701641. doi: 10.1177/1010428317701641.
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.
在本研究中，我们评估了新型八氢吡嗪并[2,1 - a:5,4 - a']二异喹啉衍生物（1 - 7）对MCF - 7和MDA - MB - 231乳腺癌细胞系的细胞毒性活性和抗增殖能力。进行膜联蛋白V结合试验和线粒体膜电位破坏试验以确定细胞凋亡情况。在用受试化合物孵育24小时后，检测半胱天冬酶3、8、9和10的活性，以解释诱导细胞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诱导细胞凋亡。我们证明了半胱天冬酶3、8、9和10的活性更高，这证实了细胞凋亡的诱导与细胞外部和内部死亡途径相关。我们的研究表明，二异喹啉衍生物组中的新型化合物通过激活外在和内在凋亡途径，有望成为抗癌治疗的候选药物。
