Bardeleben Renate V, Dunkern Torsten, Kaina Bernd, Fritz Gerhard
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany.
Int J Mol Med. 2002 Oct;10(4):473-9.
Ras-homologous GTPases are involved in the regulation of genotoxic stress-induced gene expression and cell death. Since they need C-terminal isoprenylation for correct intracellular localization and function, we investigated whether depletion of cells from isopren precursor moieties using the HMG-CoA reductase inhibitor lovastatin affects cellular sensitivity to DNA damaging drugs. Here we show that lovastatin renders cells highly resistant to the tumor-therapeutic compound doxorubicin. Desensitization by lovastatin was reverted by co-treatment with GGPP indicating that inhibition of protein geranylgeranylation is involved in acquired doxorubicin resistance. Lovastatin does not influence cellular sensitivity to DNA damaging compounds such as cisplatin, methyl methanesulfonate and ionizing radiation. The frequency of apoptotic cell death induced by doxorubicin was not affected by lovastatin as shown by both annexin V and DNA fragmentation assay. However, lovastatin releases cells from doxorubicin induced G2 blockage. Furthermore, lovastatin protects cells from doxorubicin-induced DNA strand breakage without affecting drug uptake or the expression of multidrug resistance protein (mdr-1). Since lovastatin confers cross-resistance to the topoisomerase II specific inhibitor etoposide, we suggest desensitization by the statin to be related to topoisomerase II function. The finding that lovastatin renders cells resistant to doxorubicin and etoposide by reducing their genotoxic and cytotoxic effects might have clinical implications for cancer therapy.
Ras 同源 GTP 酶参与基因毒性应激诱导的基因表达调控和细胞死亡。由于它们需要 C 末端异戊二烯化来实现正确的细胞内定位和功能，我们研究了使用 HMG-CoA 还原酶抑制剂洛伐他汀从细胞中去除异戊二烯前体部分是否会影响细胞对 DNA 损伤药物的敏感性。在此我们表明，洛伐他汀使细胞对肿瘤治疗化合物阿霉素具有高度抗性。洛伐他汀引起的脱敏作用可通过与 GGPP 共同处理而逆转，这表明蛋白质香叶基香叶基化的抑制参与了获得性阿霉素抗性。洛伐他汀不影响细胞对顺铂、甲基磺酸甲酯和电离辐射等 DNA 损伤化合物的敏感性。阿霉素诱导的凋亡细胞死亡频率不受洛伐他汀影响，膜联蛋白 V 和 DNA 片段化分析均表明了这一点。然而，洛伐他汀使细胞从阿霉素诱导的 G2 期阻滞中释放出来。此外，洛伐他汀保护细胞免受阿霉素诱导的 DNA 链断裂，而不影响药物摄取或多药耐药蛋白（mdr-1）的表达。由于洛伐他汀赋予对拓扑异构酶 II 特异性抑制剂依托泊苷的交叉抗性，我们认为他汀类药物引起的脱敏与拓扑异构酶 II 的功能有关。洛伐他汀通过降低阿霉素和依托泊苷的基因毒性和细胞毒性作用使细胞产生抗性这一发现可能对癌症治疗具有临床意义。
