School of Medicine, University of Tampere, Tampere, Finland.
Eur J Pharmacol. 2011 Dec 30;673(1-3):96-100. doi: 10.1016/j.ejphar.2011.10.022. Epub 2011 Oct 25.
Epidemiological studies have linked statin use with a decreased risk of advanced prostate cancer and an improved recurrence-free survival after radical therapy. It is unclear, however, whether statins could have direct effects against prostate cancer in a clinical setting, as their growth-inhibiting effects on prostate cancer cells have been demonstrated at drug concentrations which exceed the level in plasma during standard clinical dosing. We compared responses to high-dose and therapeutic-dose simvastatin in normal and cancerous prostate epithelial cells. Simvastatin was more effective at inhibiting the growth of normal prostate epithelial cells than of cancer cells. At therapeutic 100 nM concentration simvastatin had a cytostatic effect on normal cells: apoptosis was only slightly induced, but a decrease in cell cycle activity and an increase in senescence were observed. At therapeutic concentrations, lipophilic simvastatin caused a stronger growth inhibition than did hydrophilic rosuvastatin. In contrast, 10 μM simvastatin had a cytotoxic effect both on normal and cancer cells. Addition of LDL-cholesterol effectively reversed the cytostatic effect in all cell lines, but overcoming the cytotoxicity of 10 μM simvastatin required a combination of LDL-cholesterol and mevalonate. As LDL-cholesterol completely prevented the growth-inhibiting effect of therapeutic-dose simvastatin already at low, subphysiological concentrations it is unlikely that statins have direct effects on growth of prostate epithelial cells in vivo. Statins' possible benefits against prostate cancer could be due to systemic cholesterol-lowering, as suggested by epidemiological studies. Future clinical studies evaluating the effects of statins on prostate cancer prevention should monitor serum LDL and should probably administer statins at higher concentrations than those currently used in the treatment of hypercholesterolemia.
流行病学研究表明，他汀类药物的使用与晚期前列腺癌风险降低和根治性治疗后无复发生存率提高相关。然而，尚不清楚他汀类药物在临床环境中是否对前列腺癌有直接作用，因为其对前列腺癌细胞的生长抑制作用已在药物浓度下得到证实，该浓度超过标准临床剂量下的血浆水平。我们比较了高剂量和治疗剂量辛伐他汀在正常和癌变前列腺上皮细胞中的反应。辛伐他汀对正常前列腺上皮细胞的生长抑制作用比对癌细胞的生长抑制作用更强。在治疗浓度 100 nM 时，辛伐他汀对正常细胞具有细胞停滞作用：仅轻微诱导细胞凋亡，但观察到细胞周期活性降低和衰老增加。在治疗浓度下，亲脂性辛伐他汀比亲水性罗苏伐他汀引起更强的生长抑制作用。相比之下，10 μM 的辛伐他汀对正常细胞和癌细胞均具有细胞毒性作用。添加 LDL 胆固醇可有效逆转所有细胞系的细胞停滞作用，但要克服 10 μM 辛伐他汀的细胞毒性作用，需要 LDL 胆固醇和甲羟戊酸的组合。由于 LDL 胆固醇在低浓度（亚生理浓度）下即可完全阻止治疗剂量辛伐他汀的生长抑制作用，因此他汀类药物不太可能对体内前列腺上皮细胞的生长有直接作用。他汀类药物对前列腺癌的可能益处可能归因于系统胆固醇降低，这与流行病学研究一致。未来评估他汀类药物预防前列腺癌作用的临床研究应监测血清 LDL，并且可能需要以高于目前用于治疗高胆固醇血症的浓度来给予他汀类药物。
