Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway
Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway
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DOI：
10.1038/sj.onc.1208739
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发表时间：
2005-09-01
期刊：
影响因子：
8
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Ishitsuka, K;Hideshima, T;Anderson, KC
肌苷单磷酸脱氢酶（IMPDH）是从IMP从头合成鸟嘌呤核苷酸所需的限速酶。VX-944（Vertex Pharmaceuticals，剑桥，MA，USA）是针对人IMPDH的小分子、选择性、非竞争性抑制剂。在这份报告中，我们表明VX-944通过诱导细胞凋亡抑制人多发性骨髓瘤（MM）细胞系的体外生长。白细胞介素-6、胰岛素样生长因子-1或与骨髓基质细胞（BMSC）共培养不能防止VX-944诱导的MM细胞生长抑制。VX-944诱导MM细胞系凋亡，仅中度激活半胱天冬酶3、8和9。此外，泛半胱天冬酶抑制剂z-VAD-favorite不抑制VX-944诱导的细胞凋亡和细胞死亡。在VX-944诱导的细胞凋亡过程中，Bax和巴克的表达增强，凋亡诱导因子（AIF）和核酸内切酶G（Endo G）均从线粒体释放到胞质溶胶中，表明VX-944主要通过半胱天冬酶非依赖性Bax/AIF/Endo G途径触发MM细胞凋亡。重要的是，VX-944增强了阿霉素和美法仑的细胞毒性，即使在BMSC存在的情况下。总而言之，我们的数据表明VX-944触发了一种主要非半胱天冬酶依赖性的细胞凋亡途径，从而提供了通过将该药物与触发半胱天冬酶激活的传统药物结合来增强MM细胞细胞毒性的理论基础。
Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme required for the de novo synthesis of guanine nucleotides from IMP. VX-944 (Vertex Pharmaceuticals, Cambridge, MA, USA) is a small-molecule, selective, noncompetitive inhibitor directed against human IMPDH. In this report, we show that VX-944 inhibits in vitro growth of human multiple myeloma (MM) cell lines via induction of apoptosis. Interleukin-6, insulin-like growth factor-1, or co-culture with bone marrow stromal cells (BMSCs) do not protect against VX-944-induced MM cell growth inhibition. VX-944 induced apoptosis in MM cell lines with only modest activation of caspases 3, 8, and 9. Furthermore, the pan-caspase inhibitor z-VAD-fmk did not inhibit VX-944-induced apoptosis and cell death. During VX-944-induced apoptosis, expressions of Bax and Bak were enhanced, and both apoptosis-inducing factor (AIF) and endonuclease G (Endo G) were released from the mitochondria to cytosol, suggesting that VX-944 triggers apoptosis in MM cells primarily via a caspase-independent, Bax/AIF/Endo G pathway. Importantly, VX-944 augments the cytotoxicity of doxorubicin and melphalan even in the presence of BMSCs. Taken together, our data demonstrate a primarily non-caspase-dependent apoptotic pathway triggered by VX-944, thereby providing a rationale to enhance MM cell cytotoxicity by combining this agent with conventional agents which trigger caspase activation.