The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells
The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells
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DOI：
10.1038/sj.leu.2402501
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发表时间：
2002-07-01
期刊：
影响因子：
11.4
通讯作者：
Bloem, AC
中科院分区：
文献类型：
--
作者：
van de Donk, NWCJ;Kamphuis, MMJ;Bloem, AC
洛伐他汀是HMG-CoA还原酶的不可逆抑制剂，并阻断甲羟戊酸的产生，甲羟戊酸是胆固醇和类异戊二烯产生中的关键化合物。目标蛋白（如GTP结合蛋白Ras）的异戊烯化对于其膜定位和随后参与细胞内信号级联至关重要。洛伐他汀以剂量和时间依赖性方式有效降低细胞系（n = 10）和骨髓瘤患者样本（n = 8）中浆细胞的活力。重要的是，洛伐他汀与地塞米松的共孵育在诱导浆细胞细胞毒性方面具有协同作用。这种作用不是洛伐他汀诱导的Bcl-2或Bax蛋白表达水平变化的结果。浆细胞活力的降低是诱导凋亡和抑制增殖的结果。甲羟戊酸可有效逆转洛伐他汀对浆细胞的细胞毒性和细胞生长抑制作用。洛伐他汀的细胞毒活性在Pgp表达的细胞系中较高，但与多药耐药（MDR）相关蛋白LRP、Bcl-2和Bax无关。洛伐他汀治疗导致Ras定位从细胞膜转移到细胞质，这被甲羟戊酸逆转。本文提供的数据证明了洛伐他汀单独或与治疗药物联合治疗骨髓瘤患者的研究。
Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose- and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients.