粒体自噬
活性氧
细胞生物学
线粒体
化学
细胞生长
平衡
细胞凋亡
生物化学
生物
自噬
作者
Yena Cho,Jee Won Hwang,No-June Park,Junghyea Moon,Khan Hashim Ali,Young Ho Seo,In Su Kim,Su‐Nam Kim,Yong Kee Kim
标识
DOI:10.1016/j.freeradbiomed.2023.07.033
摘要
Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth.
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