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Anticancer Effects of a New SIRT Inhibitor, MHY2256, Against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Anticancer Effects of a New SIRT Inhibitor, MHY2256, Against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding

Eun Young Park, Youngwoo Woo, Seong Jin Kim, Do Hyun Kim, Eui Kyung Lee, Umasankar De, Kyeong Seok Kim, Jaewon Lee, Jee H Jung, Ki-Tae Ha, Wahn Soo Choi, In Su Kim, Byung Mu Lee, Sungpil Yoon, Hyung Ryong Moon, etc.

Int J Biol Sci. 2016 Dec 6;12(12):1555-1567.

PMID: 27994519

Abstract:

The sirtuins (SIRTs), a family of NAD+-dependent class III histone deacetylase, are involved in various biological processes including cell survival, division, senescence, and metabolism via activation of the stress-response pathway. Recently, inhibition of SIRTs has been considered a promising anticancer strategy, but their precise mechanisms of action are not well understood. In particular, the relevance of p53 to SIRT-induced effects has not been fully elucidated. We investigated the anticancer effects of a novel SIRT inhibitor, MHY2256, and its efficacy was compared to that of salermide in MCF-7 (wild-type p53) and SKOV-3 (null-type p53) cells. Cell viability, SIRT1 enzyme activity, cell cycle regulation, apoptosis, and autophagic cell death were measured. We compared sensitivity to cytotoxicity in MCF-7 and SKOV-3 cells. MHY2256 significantly decreased the viability of MCF-7 (IC50, 4.8 μM) and SKOV-3 (IC50, 5.6 μM) cells after a 48 h treatment period. MHY2256 showed potent inhibition (IC50, 0.27 mM) against SIRT1 enzyme activity compared with nicotinamide (IC50, >1 mM). Moreover, expression of SIRT (1, 2, or 3) protein levels was significantly reduced by MHY2256 treatment in both MCF-7 and SKOV-3 cells. Flow cytometry analysis revealed that MHY2256 significantly induced cell cycle arrest in the G1 phase, leading to an effective increase in apoptotic cell death in MCF-7 and SKOV-3 cells. A significant increase in acetylated p53, a target protein of SIRT, was observed in MCF-7 cells after MHY2256 treatment. MHY2256 up-regulated LC3-II and induced autophagic cell death in MCF-7 cells. Furthermore, MHY2256 markedly inhibited tumor growth in a tumor xenograft model of MCF-7 cells. These results suggest that a new SIRT inhibitor, MHY2256, has anticancer activity through p53 acetylation in MCF-7 human breast cancer cells.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416040	Sirtuin 7 human			Price

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