{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:51:07Z","timestamp":1790351467726,"version":"4.1.0"},"reference-count":95,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"751","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,6,12]]},"abstract":"<jats:p>\n            In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)\u2013approved voltage-gated Ca\n            <jats:sup>2+<\/jats:sup>\n            channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated\n            <jats:italic>CACNA1D<\/jats:italic>\n            and receptor-activated\n            <jats:italic>TRPC6<\/jats:italic>\n            Ca\n            <jats:sup>2+<\/jats:sup>\n            channels in CML LSCs (CD34\n            <jats:sup>+<\/jats:sup>\n            CD38\n            <jats:sup>\u2212<\/jats:sup>\n            ) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca\n            <jats:sup>2+<\/jats:sup>\n            content in CML stem\/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca\n            <jats:sup>2+<\/jats:sup>\n            uptake leads to ER and mitochondrial Ca\n            <jats:sup>2+<\/jats:sup>\n            depletion, with similar effects seen after\n            <jats:italic>CACNA1D<\/jats:italic>\n            and\n            <jats:italic>TRPC6<\/jats:italic>\n            knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adi5336","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T17:59:02Z","timestamp":1718215142000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7945-398X","authenticated-orcid":true,"given":"Ahmed","family":"Khalaf","sequence":"first","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"de Beauchamp","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-6589","authenticated-orcid":true,"given":"Eric","family":"Kalkman","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0212-0017","authenticated-orcid":true,"given":"Kevin","family":"Rattigan","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5188-8930","authenticated-orcid":true,"given":"Ekaterini","family":"Himonas","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7382-5105","authenticated-orcid":true,"given":"Joe","family":"Jones","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"James","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5932-9332","authenticated-orcid":true,"given":"Engy Shokry Abd","family":"Shokry","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7177-6960","authenticated-orcid":true,"given":"Mary T.","family":"Scott","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6532-970X","authenticated-orcid":true,"given":"Karen","family":"Dunn","sequence":"additional","affiliation":[{"name":"Paul O\u2019Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5294-8683","authenticated-orcid":true,"given":"Saverio","family":"Tardito","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."},{"name":"Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7655-016X","authenticated-orcid":true,"given":"Mhairi","family":"Copland","sequence":"additional","affiliation":[{"name":"Paul O\u2019Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9004-4079","authenticated-orcid":true,"given":"David","family":"Sumpton","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Shanks","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1616-132X","authenticated-orcid":true,"given":"G. Vignir","family":"Helgason","sequence":"additional","affiliation":[{"name":"Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0596-561"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa022457"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1609324"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70233-3"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-696013"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35721"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-326843"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-335497"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0230-9"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.659253"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.12.013"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4399"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05661-6"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0441"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0052-4"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127080"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200924"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01416-w"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-ND2019-005"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01013"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfn092"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/81834"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-021-01112-7"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2008.08.013"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140620"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-022-01277-9"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.845"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02103-8"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.01.005"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001796"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908998116"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2014"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300180200"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2017.00199"},{"issue":"1","key":"e_1_3_2_36_2","first-page":"S56","article-title":"A short history of voltage-gated calcium channels","volume":"147","author":"Dolphin A. C.","year":"2006","unstructured":"A. C. Dolphin, A short history of voltage-gated calcium channels. Br. J. Pharmacol. 147 (Suppl 1), S56\u2013S62 (2006).","journal-title":"Br. J. Pharmacol."},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02196"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0885-4505(92)90056-5"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm052"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1606"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2009.11.004"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.48.241"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1080\/03655230701596491"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0263"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2466"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.10.014"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.25.4.292"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.016"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-783845"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-40222-z"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2006.10.016"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21072327"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00071a004"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-8110com"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.2000.0301"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1815354116"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139273"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.5.1043"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a021780"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1054\/ceca.2000.0163"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35660"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd5016"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14893"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.99"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)34550-7"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.26501"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9302761"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1066957"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.26503"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.110.001917"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001742"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.09.028"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21702"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V101.2.690"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-07-655860"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2045-8"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.584232"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt009"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2016.12.012"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchromb.2013.12.026"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007489"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-019-0215-1"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.05.002"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20180421"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(02)00893-7"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202103508"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-167787"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-125455"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.11.061"},{"key":"e_1_3_2_90_2","doi-asserted-by":"crossref","unstructured":"A. I. Sheth K. Engel H. Tolison M. J. Althoff M. L. Amaya A. Krug T. Young S. Pei S. B. Patel M. Minhajuddin A. Winters R. Miller I. Shelton J. St-Germain T. Ling C. Jones B. Raught A. Gillen M. Ransom S. Staggs C. A. Smith D. A. Pollyea B. M. Stevens C. T. Jordan Targeting acute myeloid leukemia stem cells through perturbation of mitochondrial calcium. bioRxiv 10.1101\/2023.10.02.560330 (2023).","DOI":"10.1101\/2023.10.02.560330"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau7314"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1258\/ebm.2010.009362"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.018"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-020-00220-x"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab382"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.017"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adi5336","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T17:59:23Z","timestamp":1718215163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adi5336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,12]]},"references-count":95,"journal-issue":{"issue":"751","published-print":{"date-parts":[[2024,6,12]]}},"alternative-id":["10.1126\/scitranslmed.adi5336"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adi5336","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,12]]},"assertion":[{"value":"2023-05-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadi5336"}}