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Published on: February 27, 2016
SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an
Yena Cho1, Jee Won Hwang1, No-June Park2
1Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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.
Insights
SPC-180002 is a novel dual inhibitor of sirtuins (SIRTs) 1 and 3. It disrupts cellular redox homeostasis, impairs mitochondrial function, and inhibits cancer cell proliferation, offering a potential anticancer therapy.
Area of Science:
- Molecular Biology
- Cellular Biology
- Pharmacology
Background:
- Sirtuins (SIRTs) are crucial in regulating cellular redox homeostasis and are linked to reactive oxygen species (ROS) production.
- Developing selective SIRT inhibitors is vital for understanding cellular redox balance and exploring therapeutic strategies.
- Cellular redox homeostasis is a key target for cancer therapy due to its role in cell proliferation and survival.
Purpose of the Study:
- To characterize the pharmacological properties and molecular mechanism of SPC-180002 as a novel dual inhibitor of SIRT1 and SIRT3.
- To investigate the impact of SPC-180002 on cellular redox homeostasis, mitochondrial function, and cell cycle progression.
- To evaluate the anticancer efficacy of SPC-180002 in vitro and in vivo.
Main Methods:
- Pharmacological characterization of SPC-180002, a dual SIRT1/3 inhibitor.
- Assessment of ROS generation, p21 protein stability, and cell cycle progression.
- Analysis of mitophagy, mitochondrial oxygen consumption rate, and in vivo anticancer effects.
Main Results:
- SPC-180002 effectively inhibits both SIRT1 and SIRT3, leading to increased ROS generation and disturbed redox homeostasis.
- The compound enhances p21 protein stability, inhibits CDK, and disrupts cell cycle progression.
- SPC-180002 impairs mitochondrial function by inhibiting mitophagy, reducing oxygen consumption, and suppressing cancer cell proliferation in vivo.
Conclusions:
- SPC-180002 acts as a novel dual SIRT1/3 inhibitor with significant anticancer properties.
- The mechanism involves disruption of mitochondrial function and redox homeostasis, leading to cell cycle arrest.
- SPC-180002 demonstrates potent anticancer effects, highlighting its therapeutic potential.
