MHY2245, a Sirtuin Inhibitor, Induces Cell Cycle Arrest and Apoptosis in HCT116 Human Colorectal Cancer Cells.

Abstract

Sirtuins (SIRTs), which are nicotinamide adenine dinucleotide-dependent class III histone deacetylases, regulate cell division, survival, and senescence. Although sirtinol, a synthetic SIRT inhibitor, is known to exhibit antitumor effects, its mechanism of action is not well understood. Therefore, we aimed to assess the anticancer effects and underlying mechanism of MHY2245, a derivative of sirtinol, in HCT116 human colorectal cancer cells in vitro. Treatment with MHY2245 decreased SIRT1 activity and caused DNA damage, leading to the upregulation of p53 acetylation, and increased levels of p53, phosphorylation of H2A histone family member X, ataxia telangiectasia and Rad3-related kinase, checkpoint kinase 1 (Chk1), and Chk2. The level of the breast cancer type 1 susceptibility protein was also found to decrease. MHY2245 induced G2/M phase cell cycle arrest via the downregulation of cyclin B1, cell division cycle protein 2 (Cdc2), and Cdc25c. Further, MHY2245 induced HCT116 cell death via apoptosis, which was accompanied by internucleosomal DNA fragmentation, decreased B-cell lymphoma 2 (Bcl-2) levels, increased Bcl-2-asscociated X protein levels, cleavage of poly(ADP-ribose) polymerase, and activation of caspases -3, -8, and -9. Overall, MHY2245 induces cell cycle arrest, triggers apoptosis through caspase activation, and exhibits DNA damage response-associated anticancer effects.

• Authors: Yong Jung Kang, Jung Yoon Jang, Young Hoon Kwon, Jun Ho Lee, Sanggwon Lee, Yujin Park, Young-Suk Jung, Eunok Im, Hyung Ryong Moon, Hae Young Chung, Nam Deuk Kim
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 3 (Jan 29 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35163511 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Cell Cycle Proteins
• Naphthalenes
• Naphthols
• sirtinol
• Sirtuins

Topics

• Apoptosis
• Benzamides (chemistry)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, metabolism)
• Down-Regulation
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Naphthalenes (chemistry, pharmacology)
• Naphthols (chemistry)
• Sirtuins (antagonists & inhibitors)