坏死性下垂
程序性细胞死亡
细胞凋亡
细胞生物学
化学
癌症研究
细胞周期蛋白依赖激酶
流式细胞术
癌细胞
生物
分子生物学
癌症
细胞周期
生物化学
遗传学
作者
Kushal Kandhari,Jai P.N. Mishra,Rajesh Agarwal,Rana P. Singh
标识
DOI:10.1016/j.taap.2023.116409
摘要
Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mechanisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 μM) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death-inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent necroptosis in breast carcinoma cells.
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