{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:11:43Z","timestamp":1783476703718,"version":"3.55.0"},"reference-count":0,"publisher":"OAE Publishing Inc.","issue":"2","content-domain":{"domain":["oaepublish.com"],"crossmark-restriction":false},"short-container-title":["Cancer Drug Resist"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.20517\/cdr.2023.20","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T05:25:45Z","timestamp":1688448345000},"page":"430-446","update-policy":"https:\/\/doi.org\/10.20517\/oae.crossmark.policy","source":"Crossref","is-referenced-by-count":10,"title":["Statins markedly potentiate aminopeptidase inhibitor activity against (drug-resistant) human acute myeloid leukemia cells"],"prefix":"10.20517","volume":"6","author":[{"given":"Gerrit","family":"Jansen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon","family":"Al","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehuda G.","family":"Assaraf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Kammerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"van Meerloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert J.","family":"Ossenkoppele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Cloos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godefridus J.","family":"Peters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"8410","published-online":{"date-parts":[[2023]]},"container-title":["Cancer Drug Resistance"],"original-title":[],"deposited":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T08:46:30Z","timestamp":1705567590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.oaepublish.com\/articles\/cdr.2023.20"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023]]},"references-count":0,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023]]}},"URL":"https:\/\/doi.org\/10.20517\/cdr.2023.20","relation":{},"ISSN":["2578-532X"],"issn-type":[{"value":"2578-532X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023]]}}}