Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, Shaanxi 710061, China; Laboratory Animal Center, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Department of Pharmacy, Eighth Hospital of Xi'an City, Xi'an, Shaanxi 710061, China.
Cancer Lett. 2015 Jan 28;356(2 Pt B):791-9. doi: 10.1016/j.canlet.2014.10.033. Epub 2014 Oct 31.
Imatinib (IM) represents a breakthrough in the treatment of chronic myeloid leukemia (CML) by inhibiting the activity of Bcr-Abl tyrosine kinase. However, many patients exhibit resistance to IM in the clinic. Recent studies have indicated that sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), plays an important role in leukemogenesis. In addition, some HDAC inhibitors are being tested to determine their anti-cancer activities in clinical trials. Divalproex sodium (DVPX), a first-line treatment for epilepsy, is also a HDAC inhibitor. However, it is unclear whether the anti-leukemic effects of IM in combination with DVPX on CML cells are related to SIRT1. The aim of this study was to investigate the effects of IM in combination with DVPX on cell viability, apoptosis, and cell cycle arrest in CML cells and to explore the underlying mechanisms. It was found that DVPX enhanced IM-induced cell growth inhibition, apoptosis and cell cycle arrest in K562-S and K562-G cells. Surprisingly, the level of p-Bcr-Abl was similar in K562-S and K562-G cells. Moreover, IM combined with DVPX had no effects on the phosphorylation of Bcr-Abl and its downstream target STAT5. Further study revealed that SIRT1 expression was higher in K562-G cells compared with K562-S cells. DVPX enhanced the inhibitory effect of IM on SIRT1 expression in K562-S and K562-G cells. Furthermore, knockdown of SIRT1 promoted apoptosis of K562-G cells treated with IM and DVPX. These results indicate that DVPX may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating SIRT1 expression.
伊马替尼 (IM) 通过抑制 Bcr-Abl 酪氨酸激酶的活性，代表了治疗慢性髓性白血病 (CML) 的突破。然而，许多患者在临床上对 IM 表现出耐药性。最近的研究表明，组蛋白去乙酰化酶 (HDAC) Ⅲ类的 Sirtuin 1 (SIRT1) 在白血病发生中起着重要作用。此外，一些 HDAC 抑制剂正在进行临床试验，以确定其抗癌活性。丙戊酸钠 (DVPX) 是治疗癫痫的一线药物，也是一种 HDAC 抑制剂。然而，目前尚不清楚 IM 与 DVPX 联合应用对 CML 细胞的抗白血病作用是否与 SIRT1 有关。本研究旨在探讨 IM 与 DVPX 联合应用对 CML 细胞活力、凋亡和细胞周期阻滞的影响，并探讨其潜在机制。结果发现，DVPX 增强了 IM 对 K562-S 和 K562-G 细胞生长抑制、凋亡和细胞周期阻滞的作用。令人惊讶的是，K562-S 和 K562-G 细胞中的 p-Bcr-Abl 水平相似。此外，IM 与 DVPX 联合应用对 Bcr-Abl 及其下游靶点 STAT5 的磷酸化无影响。进一步研究表明，与 K562-S 细胞相比，K562-G 细胞中 SIRT1 表达水平更高。DVPX 增强了 IM 对 K562-S 和 K562-G 细胞中 SIRT1 表达的抑制作用。此外，沉默 SIRT1 促进了 IM 和 DVPX 处理的 K562-G 细胞的凋亡。这些结果表明，DVPX 可能通过调节 SIRT1 表达增加 CML 细胞对 IM 的敏感性，并逆转 IM 耐药性。
