Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells  

作　　者：Gerrit Jansen Marjon Al Yehuda G.Assaraf Sarah Kammerer Johan van Meerloo Gert J.Ossenkoppele Jacqueline Cloos Godefridus J.Peters 

机构地区：[1]Department of Rheumatology and Clinical Immunology,Amsterdam Rheumatology and immunology Center,Amsterdam University Medical Center,location VUmc,Amsterdam 1081 HV,The Netherlands [2]The Fred Wyszkowsky Cancer Research Laboratory,Faculty of Biology,The Technion-Israel Institute of Technology,Haifa 3200003,Israel [3]Department of Medical Oncology,Amsterdam University Medical Center,location VUmc,Amsterdam 1081 HV,The Netherlands [4]Institute of Biotechnology,Molecular Cell Biology,Brandenburg University of Technology Cottbus-Senftenberg,Senftenberg 01968,Germany [5]Department of Hematology,Amsterdam University Medical Center,location VUmc,Amsterdam 1081 HV,The Netherlands [6]Department of Biochemistry,Medical University of Gdansk,Gdansk 80-210,Poland

出　　处：《Cancer Drug Resistance》2023年第3期430-446,共17页癌症耐药（英文）

基　　金：This study was supported by Cancer Center Amsterdam grants 07/36 and 2012-1-08.

摘　　要：Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells.Methods: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR activation.Results: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by simvastatin.Conclusion: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

关 键 词：AMINOPEPTIDASE STATINS mevalonate pathway carboxyl esterase RHEB mTOR 

分 类 号：R733.71[医药卫生—肿瘤]