Fritz Gerhard
Department of Toxicology, University of Mainz, D-55131 Mainz, Germany.
Int J Oncol. 2005 Nov;27(5):1401-9.
Apart from their lipid lowering activity, HMG-CoA reductase inhibitors (statins) impair numerous cellular functions associated with metastasis, e.g. gene expression, angiogenesis, cell adhesion, cell motility and invasiveness. Furthermore, statins have impact on apoptotic cell death and modulate cellular susceptibility to cell killing by anticancer drugs and ionizing radiation. Part of the effects provoked by statins are due to the inhibition of the prenylation of low molecular weight GTPases, in particular Ras and Rho, which play key roles in signaling evoked by stimulation of cell surface receptors. C-terminal lipid modification of Ras/Rho GTPases is essential for their correct intracellular localization and function. By depletion of the cellular pool of isoprene precursor molecules, statins reduce the level of membrane-bound active Ras/Rho proteins, thereby impairing corresponding functions. Since broad clinical experience already exists for statins, their incorporation into established tumor-therapeutic regimens would be realizable in a rather short period of time. Here, data available at present arguing for the usefulness of statins in anticancer therapy are summarized and discussed.
除了其降脂活性外，HMG-CoA还原酶抑制剂（他汀类药物）还会损害许多与转移相关的细胞功能，例如基因表达、血管生成、细胞黏附、细胞运动性和侵袭性。此外，他汀类药物对凋亡性细胞死亡有影响，并调节细胞对抗癌药物和电离辐射诱导的细胞杀伤的敏感性。他汀类药物引发的部分效应是由于抑制了低分子量GTP酶的异戊二烯化，特别是Ras和Rho，它们在细胞表面受体刺激引发的信号传导中起关键作用。Ras/Rho GTP酶的C末端脂质修饰对于其正确的细胞内定位和功能至关重要。通过消耗细胞内异戊二烯前体分子池，他汀类药物降低了膜结合活性Ras/Rho蛋白的水平，从而损害相应功能。由于他汀类药物已有广泛的临床经验，将其纳入既定的肿瘤治疗方案在相当短的时间内是可行的。在此，总结并讨论了目前支持他汀类药物在抗癌治疗中有用性的现有数据。
