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Abstract
We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC50 values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. 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. A 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 the number of 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.
Highlights
Endometrial cancer is one of the most common gynecological malignancies, affecting approximately 142,000 women and causing an estimated 42,000 deaths worldwide [1,2]
The measured IC50 value of MHY2256 against Ishikawa cells was 5.6 μM, which is approximately 10-fold lower than that of salermide. These results suggest that MHY2256 is highly cytotoxic towards endometric cancer cells
MHY2256 Induces Autophagic Cell Death We previously showed that MHY2256 significantly increases the autophagic cell death of breast cancer cells [16]
Summary
Endometrial cancer is one of the most common gynecological malignancies, affecting approximately 142,000 women and causing an estimated 42,000 deaths worldwide [1,2]. Endometrial cancer was extensively studied at the molecular level to develop effective therapies using histone deacetylase (HDAC) inhibitors, which have shown their potential as therapeutic agents for endometrial cancer [7,8]. HDACs play an important role in regulating the epigenetic processes that lead to the expression of target genes in the development of multiple cancers [9,10]. Numerous HDAC inhibitors have been evaluated in clinical studies for the treatment of breast, cervical, and ovarian cancers, which are commonly correlated with hormone-dependent cancers in women. A novel synthesized class III HDAC inhibitor, MHY2256 (Figure 1A), reduced breast and ovarian cancer cell proliferation and induced apoptosis [16]. The exact role of class III HDAC sirtuin (SIRT) in p53 activation in endometrial cancer remains unclear
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