Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 150, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2022.112928
Keywords
VDAC; Mitochondrial metabolism; Cancer; NADH-binding pocket; Mitochondrial dysfunction
Funding
- U.S. National Institutes of Health (NIH/NCI) [RO1 CA184456]
- South Carolina Translational Research Pilot Project [UL1 TR001450-SCTR]
- Chan Zuckerberg Foundation Imaging Scientist Award
- Abney Foundation Fellowship from MUSC Hollings Cancer Center
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In this study, a novel small molecule targeting VDAC, SC18, was identified, which can induce mitochondrial dysfunction and inhibit cell proliferation in liver cancer cells.
Voltage dependent anion channels (VDAC) control the flux of most anionic respiratory substrates, ATP, ADP, and small cations, crossing the outer mitochondrial membrane. VDAC closure contributes to the partial suppression of mitochondrial metabolism that favors the Warburg phenotype of cancer cells. Recently, it has been shown that NADH binds to a specific pocket in the inner surface of VDAC1, also conserved in VDAC2 and 3, closing the channel. We hypothesized that binding of small molecules to the NADH pocket, maintain VDAC in an open configuration by preventing closure induced by NADH and possible other endogenous regulators. We screened in silico, the South Carolina Compound Collection SC3 (~100,000 proprietary molecules), using shape-based queries of the NADH binding region of VDAC. After molecular docking of selected compounds, we physically screened candidates using mitochondrial membrane potential (Delta psi m), as an overall readout of mitochondrial metabolism. We identified SC18, as the most potent compound. SC18 bound to VDAC1, as assessed by a thermal shift assay. Short-term treatment with SC18 decreased Delta psi m in SNU-449 and HepG2 human hepatocarcinoma cells. Mitochondrial depolarization was similar in wild type, VDAC1/2, 1/3, and 2/3 double KO HepG2 cells indicating that the effect of SC18 was not VDAC isoform-dependent. In addition, SC18 decreased mitochondrial NADH and cellular ATP production; and increased basal respiration. Long-term exposure to SC18, decreased cell proliferation as determined by wound-healing and cell viability assays. In summary, SC18 is a novel VDACtargeting small molecule that induces mitochondrial dysfunction and inhibits cell proliferation.
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