Fluvastatin, a lipophilic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, suppresses proliferation and induces apoptosis in various cancer cells[1-2]. Fluvastatin, which structurally mimics HMG-CoA to competitively block the enzyme’s active site, lowers total and low-density lipoprotein (LDL) cholesterol while exerting anti-atherogenic, antithrombotic, and antioxidant effects and improving vascular function[2-3].
In vitro, after 72h of treatment with the increasing concentrations of Fluvastatin (5, 10, and 20μM), human endometrial cancer (EC) cells exhibited a concentration-dependent decline in viability and proliferation, markedly reduced migration and invasion, and elevated apoptosis accompanied by progressive up-regulation of p53 and cleaved caspase-3[4]. A 24h incubation with 2.5μM Fluvastatin reproducibly gave over 50% inhibition of thrombin-induced von Willebrand factor (vWF) secretion, was more effective than shorter incubation times, did not disrupt the human umbilical-vein endothelial cells (HUVEC) culture monolayer, and did not change vWF antigen levels measured in cell lysates[5].
In vivo, after four daily intraperitoneal injections of 10mg/kg Fluvastatin in female C57BL/6J mice, total peritoneal cell counts remained unchanged, yet the proportion and absolute number of mast cells recovered from peritoneal lavage were markedly reduced[6]. The rats treated by gavage with 10mg/kg Fluvastatin showed a reduced number of polymorphonuclear neutrophils (PMN) compared to the control rats at 4h postinjection[7].
References:
[1] Zhang W, Wu J, Zhou L, et al. Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway. Indian J Exp Biol. 2010;48(12):1167-1174.
[2] Langtry HD, Markham A. Fluvastatin: a review of its use in lipid disorders. Drugs. 1999;57(4):583-606.
[3] Bonds M, Bordoni B. Fluvastatin. In: StatPearls. StatPearls Publishing; 2023.
[4] Cai Y, Zhao F. Fluvastatin suppresses the proliferation, invasion, and migration and promotes the apoptosis of endometrial cancer cells by upregulating Sirtuin 6 (SIRT6). Bioengineered. 2021;12(2):12509-12520.
[5] Fish RJ, Yang H, Viglino C, et al. Fluvastatin inhibits regulated secretion of endothelial cell von Willebrand factor in response to diverse secretagogues. Biochem J. 2007;405(3):597-604.
[6] Paez PA, Kolawole M, Taruselli MT, et al. Fluvastatin Induces Apoptosis in Primary and Transformed Mast Cells. J Pharmacol Exp Ther. 2020;374(1):104-112.
[7] Fischetti F, Carretta R, Borotto G, et al. Fluvastatin treatment inhibits leucocyte adhesion and extravasation in models of complement-mediated acute inflammation. Clin Exp Immunol. 2004;135(2):186-193.
Fluvastatin是一种亲脂性的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，可在多种癌细胞中抑制增殖并诱导凋亡[1-2]。Fluvastatin分子结构模拟HMG-CoA，通过竞争性占据酶的活性位点，降低总胆固醇和低密度脂蛋白（LDL）胆固醇水平，同时发挥抗动脉粥样硬化、抗血栓及抗氧化作用，并改善血管功能[2-3]。
在体外，对人子宫内膜癌（EC）细胞给予5、10和20μM递增浓度的Fluvastatin处理72小时后，细胞的存活率和增殖能力呈浓度依赖性下降，迁移和侵袭能力显著削弱，细胞凋亡水平升高，且p53和剪切型caspase-3表达逐步上调[4]。将人脐静脉内皮细胞（HUVEC）与2.5μM的Fluvastatin共孵育24小时，可稳定地抑制凝血酶诱导的血管性血友病因子（vWF）分泌超过50%，抑制效果优于更短孵育时间，且既不破坏HUVEC单层结构，也不改变细胞裂解液中的vWF抗原水平[5]。
在体内，对雌C57BL/6J小鼠连续4天腹腔注射10mg/kg的Fluvastatin后，腹腔总细胞数未见变化，但灌洗液中肥大细胞的比例和绝对数量均显著减少[6]。经灌胃给予10mg/kg的Fluvastatin大鼠，在注射后4小时，其多形核中性粒细胞（PMN）数量较对照组显著下降[7]。