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SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity

Authors
Cho, YenaHwang, Jee WonPark, No-JuneMoon, JunghyeaAli, Khan HashimSeo, Young HoKim, In SuKim, Su-NamKee, Yong
Issue Date
Nov-2023
Publisher
ELSEVIER SCIENCE INC
Keywords
SIRT1/3 dual inhibitor; SPC-180002; Mitochondrial dynamics; Cellular respiration; Redox homeostasis; Mitophagy
Citation
FREE RADICAL BIOLOGY AND MEDICINE, v.208, pp 73 - 87
Pages
15
Journal Title
FREE RADICAL BIOLOGY AND MEDICINE
Volume
208
Start Page
73
End Page
87
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/151548
DOI
10.1016/j.freeradbiomed.2023.07.033
ISSN
0891-5849
1873-4596
Abstract
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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