A New Synthetic Histone Deacetylase Inhibitor, MHY2256, Induces Apoptosis and Autophagy Cell Death in Endometrial Cancer Cells via p53 Acetylation

Abstract

We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

“…This is in accordance with findings of Lara and coworkers [47], who showed that SIRT1inhibitors can induce massive apoptosis in p53-dependentcancers, but not in p53-independent cells. Our previous study showed the strongest induction of apoptosis in MCF-7 cells after treatment with salermide, a SIRT1 inhibitor, but SKOV3 cells showed only about a 10% increase in apoptosis [45,[48][49][50]. It appears that this observation in MCF-7 cells was due to the presence of the wild-type p53, since p53-deficient SKOV3 cells show only a small increase in apoptosis due to salermide [51].…”

Targeting CDK9: A novel biomarker in�the�treatment of endometrial cancer

“…Surgery is the main treatment for endometrial cancer. Most patients in the early stage can be cured by surgery, but treatment is limited for patients with metastasis and recurrence (23). It is widely recognized that laparoscopy is superior to laparotomy in most patients with endometrial cancer.…”

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

“…A quinoxaline-based compound 4bb selectively reduces colon cancer cell viability without affecting normal fibroblasts (Ghosh et al, 2017). Moreover, MHY2256, a potent SIRT1 inhibitor, significantly inhibits growth of endometrial and breast cancer cells (De et al, 2018;. Recently, a new SIRT7 inhibitor (ID: 97491) has been identified that shows potent inhibitory effect on cancer growth by upregulating apoptosis (Kim et al, 2019).…”

“…Recently, a new SIRT7 inhibitor (ID: 97491) has been identified that shows potent inhibitory effect on cancer growth by upregulating apoptosis (Kim et al, 2019). All these compounds work partially via promoting acetylation and activation of p53, thereby driving cell cycle arrest and inducing apoptotic or autophagic cell death (De et al, 2018;Ghosh et al, 2017;Kim et al, 2019;Tae et al, 2018).…”