title: Anticancer Effects of a New SIRT Inhibitor, MHY2256, against Human Breast Cancer MCF-7 Cells via Regulation of MDM2-p53 Binding.
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.
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Youngwoo
authors.initials: Y
authors.lastname: Woo
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Do Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Eui Kyung
authors.initials: EK
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Umasankar
authors.initials: U
authors.lastname: De
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Kyeong Seok
authors.initials: KS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Department of Korean Medical Science, School of Korean Medicine and Korean Medicine Research Center for Healthy Aging, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea.
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
authors.affiliation: Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: In Su
authors.initials: IS
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Pusan National University, San 30, Jangjeon-dong, Geumjeung-gu, Busan, 609-735, Republic of Korea.
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D037761:Sirtuins
keywords: MDM2; MHY2256; SIRT inhibitor; apoptosis; autophagy.; p53