School of Pharmacy, Sungkyunkwan University, 2066, Seobu-ro, Jangan-gu, Suwon 16419, Korea.
College of Pharmacy, Pusan National University, Busandaehak-ro 63 beon-gil 2, Geumjeong-gu, Busan 46241, Korea.
Int J Mol Sci. 2018 Sep 13;19(9):2743. doi: 10.3390/ijms19092743.
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 IC 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.
我们之前发现了一种新型的 Sirtuin（SIRT）抑制剂 MHY2256，它通过 MCF-7 人乳腺癌细胞中的 p53 乙酰化发挥抗癌活性。我们研究了 MHY2256 对激素相关癌症（一种预后较差的子宫内膜癌）的抗癌活性。MHY2256 的 IC 值明显低于著名的 SIRT 抑制剂 Ssalermide。此外，MHY2256 显著降低了 SIRT1、2 和 3 的蛋白表达和活性，与 Ssalermide 的效果相似。特别是，MHY2256 显著抑制了 Ishikawa 癌细胞肿瘤异种移植小鼠模型中的肿瘤生长。在实验期间，用 MHY2256 治疗的小鼠的体重没有明显变化。对 Ishikawa 细胞的敏化机制的详细分析表明，晚期细胞凋亡被 MHY2256 大大增加。此外，MHY2256 增加了 G1 期阻滞并减少了细胞周期相关蛋白的数量，表明 MHY2256 通过细胞阻滞实现了细胞凋亡。特别是，MHY2256 大大增加了 p21，表明细胞周期阻滞是 MHY2256 在 Ishikawa 细胞中敏化的主要因素。我们还检测到在 MHY2256 处理后 Ishikawa 细胞中乙酰化 p53（SIRT1 的靶蛋白）显著增加。在小鼠异种移植模型中，MHY2256 显著减少了肿瘤生长和重量，没有明显的副作用。这些结果表明，MHY2256 通过 p53 乙酰化在子宫内膜癌中发挥抗癌活性，可用于针对激素相关癌症。
