Guangzhou Jinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
Chem Biol Interact. 2013 Sep 5;205(1):1-10. doi: 10.1016/j.cbi.2013.06.007. Epub 2013 Jun 15.
Heat shock protein 90 (Hsp90) serves as an ATP-dependent molecular chaperone for numerous cell signaling proteins, including many oncogenes and clinically validated cancer targets that are involved in cell proliferation and survival. Recent studies have shown that the Hsp90 inhibitor, SNX-2112, effectively inhibits tumor cell growth and angiogenesis in hematological and solid tumors. However, little is known about the effects of SNX-2112 on leukemias that are resistant to chemotherapy, which is emerging as a major clinical problem. In this study, the effects of SNX-2112 on the multidrug-resistant human chronic myeloid leukemia (CML) K562/ADR cell line were investigated. We observed that SNX-2112 exhibited dose- and time-dependent inhibitory activities against K562/ADR cells. These effects included the induction of apoptosis and secondary necrosis in addition to cell cycle arrest at the G1 and G2 phases. Furthermore, SNX-2112-induced apoptosis was predominantly mediated by the mitochondrial pathway, initiated by the release of cytochrome c and the participation of Bcl-2 family proteins. SNX-2112 also induced the activation of the caspase-3, -8 and -9 cascade and the subsequent cleavage of PARP in K562/ADR cells. Moreover, the inactivation of the Akt and NF-κB signaling pathways may be involved in SNX-2112-induced apoptosis. The expression levels of P-glycoprotein (P-gp) and several chaperons related to drug resistance and apoptosis were also shown to be inhibited, including the Grp78 and Hsp90 isoforms, Grp94 and Trap1. Taken together, these results provide a possible molecular mechanism for the anti-cancer effect of SNX-2112 on K562/ADR cells and provide new insights into the future application of SNX-2112 as a therapeutic agent for anti-multidrug-resistant leukemias.
热休克蛋白 90（Hsp90）作为一种依赖于 ATP 的分子伴侣，可用于多种细胞信号蛋白，包括许多癌基因和经临床验证的癌症靶点，这些蛋白参与细胞增殖和存活。最近的研究表明，Hsp90 抑制剂 SNX-2112 可有效抑制血液系统和实体肿瘤中的肿瘤细胞生长和血管生成。然而，对于对化疗耐药的白血病，SNX-2112 的作用知之甚少，这是一个日益严重的临床问题。在这项研究中，研究了 SNX-2112 对多药耐药人慢性髓系白血病（CML）K562/ADR 细胞系的影响。我们观察到 SNX-2112 对 K562/ADR 细胞表现出剂量和时间依赖性的抑制活性。这些作用包括诱导凋亡和继发性坏死，以及细胞周期在 G1 和 G2 期停滞。此外，SNX-2112 诱导的凋亡主要通过线粒体途径介导，该途径由细胞色素 c 的释放和 Bcl-2 家族蛋白的参与引发。SNX-2112 还诱导 K562/ADR 细胞中 caspase-3、-8 和 -9 级联的激活以及随后 PARP 的裂解。此外，Akt 和 NF-κB 信号通路的失活可能参与了 SNX-2112 诱导的凋亡。还显示 P-糖蛋白（P-gp）和几种与耐药性和凋亡相关的伴侣的表达水平受到抑制，包括 Grp78 和 Hsp90 同工型、Grp94 和 Trap1。总之，这些结果为 SNX-2112 对 K562/ADR 细胞的抗癌作用提供了可能的分子机制，并为 SNX-2112 作为治疗多药耐药性白血病的药物的未来应用提供了新的见解。
