Ludwig Boltzmann Cluster Oncology, Hanusch Hospital, Vienna 1140, Austria.
Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna 1140, Austria.
Int J Mol Sci. 2017 Sep 15;18(9):1982. doi: 10.3390/ijms18091982.
Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP⁺/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.
他汀类药物和双膦酸盐类药物越来越被认为是抗癌药物，尤其是因为它们具有降低胆固醇的特性。然而，这些药物对不同类型的癌症的作用方式不同。因此，本研究旨在比较他汀类药物和双膦酸盐类药物对不同来源（前列腺癌 PC-3 细胞、乳腺癌 MDA-MB-231 细胞、骨肉瘤 U-2 OS 细胞）高增殖肿瘤细胞系与增殖速度较慢的细胞（骨肉瘤 MG-63 细胞）代谢（NADP⁺/NADPH 关系）的影响。全基因表达分析显示，用药物剂量的他汀类药物辛伐他汀和双膦酸盐伊班膦酸钠处理 6 天后，辛伐他汀调节的基因数量是伊班膦酸钠的两倍多，包括许多与细胞周期进程相关的基因。在快速生长的癌细胞系中，饥饿标志物的上调、代谢和相关 NADPH 产生的减少、自噬的增加以及 H3K27 甲基化的伴随下调最为显著。本研究为临床观察提供了可能的解释，表明快速增殖的肿瘤对他汀类药物和双膦酸盐类药物更为敏感。
