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首页> 外文期刊>Molecular cancer therapeutics >Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma.
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Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma.

机译：对洛伐他汀诱导的多发性骨髓瘤细胞凋亡敏感性的决定因素。

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Statins, commonly used to treat hypercholesterolemia, have been shown to trigger tumor-specific apoptosis in certain cancers, including multiple myeloma (MM), a plasma cell malignancy with poor prognosis. In this article, we show that of a panel of 17 genetically distinct MM cell lines, half were sensitive to statin-induced apoptosis and, despite pharmacodynamic evidence of drug uptake and activity, the remainder were insensitive. Sensitive cells were rescued from lovastatin-induced apoptosis by mevalonate, geranylgeranyl PPi, and partially by farnesyl PPi, highlighting the importance of isoprenylation. Expression profiling revealed that Rho GTPase mRNAs were differentially expressed upon lovastatin exposure in sensitive cells, yet ectopic expression of constitutively active Rho or Ras proteins was insufficient to alter sensitivity to lovastatin-induced apoptosis. This suggests that sensitivity involves more than one isoprenylated protein and that statins trigger apoptosis by blocking many signaling cascades, directly or indirectly deregulated by the oncogenic lesions of the tumor cell. Indeed, clustering on the basis of genetic abnormalities was shown to be significantly associated with sensitivity (P = 0.003). These results suggest that statins may be a useful molecular targeted therapy in the treatment of a subset of MM.
机译：他汀类药物通常用于治疗高胆固醇血症，已显示在某些癌症中触发肿瘤特异性凋亡，包括多发性骨髓瘤（MM），即预后不良的浆细胞恶性肿瘤。在本文中，我们显示了一组17种遗传上不同的MM细胞系，其中一半对他汀类药物诱导的细胞凋亡敏感，尽管有药物吸收和活性的药效学证据，其余的都不敏感。甲羟戊酸，香叶基香叶基PPi和部分法呢基PPi可从洛伐他汀诱导的细胞凋亡中拯救敏感细胞，从而突出了异戊二烯化的重要性。表达谱分析表明，在洛伐他汀暴露后，Rho GTPase mRNA在敏感细胞中差异表达，而组成型活性Rho或Ras蛋白的异位表达不足以改变对洛伐他汀诱导的细胞凋亡的敏感性。这表明敏感性涉及一种以上的异戊二烯基化蛋白，他汀类药物通过阻断许多信号级联反应来触发凋亡，而这些信号级联反应直接或间接地被肿瘤细胞的致癌性损伤所调节。确实，基于遗传异常的聚类被证明与敏感性显着相关（P = 0.003）。这些结果表明，他汀类药物可能是治疗一部分MM的有用分子靶向疗法。

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