{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:54:17Z","timestamp":1790463257013,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 \u03b1- and 5,6 \u03b2-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients\u2019 sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 \u03b1-EC and 5,6 \u03b2-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 \u03b1-EC and 5,6 \u03b2-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 \u03b1-EC and 5,6 \u03b2-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM.<\/jats:p>","DOI":"10.3390\/cancers13153747","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T09:25:52Z","timestamp":1627291552000},"page":"3747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0653-3791","authenticated-orcid":false,"given":"Oumaima","family":"Jaouadi","sequence":"first","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e8s","family":"Limam","sequence":"additional","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-6083","authenticated-orcid":false,"given":"Mohamed","family":"Abdelkarim","sequence":"additional","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emna","family":"Berred","sequence":"additional","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"},{"name":"Department of Clinical Hematology, Aziza Othmana Hospital, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahlem","family":"Chahbi","sequence":"additional","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-4665","authenticated-orcid":false,"given":"M\u00e9lody","family":"Caillot","sequence":"additional","affiliation":[{"name":"Normandie University, INSERM U1245, Unicaen, F-14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7278-9651","authenticated-orcid":false,"given":"Brigitte","family":"Sola","sequence":"additional","affiliation":[{"name":"Normandie University, INSERM U1245, Unicaen, F-14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Ben Aissa-Fennira","sequence":"additional","affiliation":[{"name":"Laboratory of Oncohematology, PRF of Oncohematology, Faculty of Medicine of Tunis, Tunis El Manar University, Tunis 1006, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41408-020-00359-2","article-title":"Multiple Myeloma Current Treatment Algorithms","volume":"10","author":"Rajkumar","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-3-030-38266-7_6","article-title":"Resistance to the Proteasome Inhibitors: Lessons from Multiple Myeloma and Mantle Cell Lymphoma","volume":"1233","author":"Quinet","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ramasamy, K., Gay, F., Weisel, K., Zweegman, S., Mateos, M.V., and Richardson, P. (2021). Improving Outcomes for Patients with Relapsed Multiple Myeloma: Challenges and Considerations of Current and Emerging Treatment Options. Blood Rev., 100808.","DOI":"10.1016\/j.blre.2021.100808"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S1470-2045(20)30756-7","article-title":"Treatment of Relapsed and Refractory Multiple Myeloma: Recommendations from the International Myeloma Working Group","volume":"22","author":"Moreau","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.bcp.2013.02.029","article-title":"Oxysterols in Cancer Cell Proliferation and Death","volume":"86","author":"Fabre","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Choi, T., Choi, I.Y., Han, K., Jeong, S.-M., Yoo, J.E., Rhee, S.Y., Park, Y.-G., and Shin, D.W. (2021). Lipid Level, Lipid Variability, and Risk of Multiple Myeloma: A Nationwide Population-Based Study of 3,527,776 Subjects. Cancers, 13.","DOI":"10.3390\/cancers13030540"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.biochi.2012.05.006","article-title":"Cholesterol-5,6-Epoxides: Chemistry, Biochemistry, Metabolic Fate and Cancer","volume":"95","author":"Poirot","year":"2013","journal-title":"Biochimie"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1016\/j.fct.2010.09.023","article-title":"Oxysterols: A World to Explore","volume":"48","author":"Ansorena","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nury, T., Zarrouk, A., Yammine, A., Mackrill, J.J., Vejux, A., and Lizard, G. (2020). Oxiapoptophagy: A Type of Cell Death Induced by Some Oxysterols. Br. J. Pharmacol.","DOI":"10.1111\/bph.15173"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.plipres.2016.09.002","article-title":"Oxysterols: From Cholesterol Metabolites to Key Mediators","volume":"64","author":"Mutemberezi","year":"2016","journal-title":"Prog. Lipid. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10565-005-0141-2","article-title":"Comparison of the Cytotoxic, pro-Oxidant and pro-Inflammatory Characteristics of Different Oxysterols","volume":"21","author":"Prunet","year":"2005","journal-title":"Cell Biol. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.bcp.2013.02.031","article-title":"5,6-Epoxy-Cholesterols Contribute to the Anticancer Pharmacology of Tamoxifen in Breast Cancer Cells","volume":"86","author":"Segala","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"911","DOI":"10.18632\/oncotarget.1066","article-title":"Antiestrogen-Binding Site Ligands Induce Autophagy in Myeloma Cells That Proceeds through Alteration of Cholesterol Metabolism","volume":"4","author":"Sola","year":"2013","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.reprotox.2006.05.006","article-title":"Induction of Apoptosis by 25-Hydroxycholesterol in Adult Rat Leydig Cells: Protective Effect of 17\u03b2-Estradiol","volume":"22","author":"Travert","year":"2006","journal-title":"Reprod. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/BF00238433","article-title":"Differential Sensitivity of Astrocyte Primary Cultures and Derived Spontaneous Transformed Cell Lines to 70-Hydroxycholesterol: Effect on Plasma Membrane Lipid Composition and Fluidity, and on Cell Surface Protein Expression","volume":"101","author":"Kupferberg","year":"1991","journal-title":"Mol. Cell Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1194\/jlr.M023689","article-title":"Surprising Unreactivity of Cholesterol-5,6-Epoxides towards Nucleophiles","volume":"53","author":"Paillasse","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.coph.2012.07.007","article-title":"Cholesterol Epoxide Hydrolase and Cancer","volume":"12","author":"Poirot","year":"2012","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Caillot, M., Zylbersztejn, F., Maitre, E., Bourgeais, J., H\u00e9rault, O., and Sola, B. (2020). ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance. Cells, 9.","DOI":"10.3390\/cells9112357"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101145","DOI":"10.1016\/j.eujim.2020.101145","article-title":"Olea Europaea L. Cv. Chetoui Leaf and Stem Hydromethanolic Extracts Suppress Proliferation and Promote Apoptosis via Caspase Signaling on Human Multiple Myeloma Cells","volume":"37","author":"Limam","year":"2020","journal-title":"Eur. J. Integr. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Limam, I., Ben Aissa-Fennira, F., Essid, R., Chahbi, A., Kefi, S., Mkadmini, K., Elkahoui, S., and Abdelkarim, M. (2021). Hydromethanolic Root and Aerial Part Extracts from Echium Arenarium Guss Suppress Proliferation and Induce Apoptosis of Multiple Myeloma Cells through Mitochondrial Pathway. Environ. Toxicol.","DOI":"10.1002\/tox.23090"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/cyto.990210308","article-title":"Kinetics of Plasma Membrane and Mitochondrial Alterations in Cells Undergoing Apoptosis","volume":"21","author":"Lizard","year":"1995","journal-title":"Cytometry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2121-14-32","article-title":"Caspase-9, Caspase-3 and Caspase-7 Have Distinct Roles during Intrinsic Apoptosis","volume":"14","author":"Brentnall","year":"2013","journal-title":"BMC Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Brown, A.J., Sharpe, L.J., and Rogers, M.J. (2020). Oxysterols: From Physiological Tuners to Pharmacological Opportunities. Br. J. Pharmacol.","DOI":"10.1111\/bph.15073"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.bbrc.2018.10.008","article-title":"Oxysterols Selectively Promote Short-Term Apoptosis in Tumor Cell Lines","volume":"505","author":"Levy","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jprot.2016.06.011","article-title":"7-Ketocholesterol Overcomes Drug Resistance in Chronic Myeloid Leukemia Cell Lines beyond MDR1 Mechanism","volume":"151","author":"Fernandes","year":"2017","journal-title":"J. Proteom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/jbt.20096","article-title":"Activation of Caspase-3-Dependent and -Independent Pathways during 7-Ketocholesterol- and 7\u03b2-Hydroxycholesterol-Induced Cell Death: A Morphological and Biochemical Study","volume":"19","author":"Prunet","year":"2005","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3390\/biom2010076","article-title":"Oxysterols and Their Cellular Effectors","volume":"2","author":"Olkkonen","year":"2012","journal-title":"Biomolecules"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Caillot, M., Dakik, H., Mazurier, F., and Sola, B. (2021). Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death. Cancers, 13.","DOI":"10.3390\/cancers13102411"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1080\/10715762.2019.1612891","article-title":"Biotin Attenuation of Oxidative Stress, Mitochondrial Dysfunction, Lipid Metabolism Alteration and 7\u03b2-Hydroxycholesterol-Induced Cell Death in 158N Murine Oligodendrocytes","volume":"53","author":"Sghaier","year":"2019","journal-title":"Free Radic. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Michallet, A.-S., Mondiere, P., Taillardet, M., Leverrier, Y., Genestier, L., and Defrance, T. (2011). Compromising the Unfolded Protein Response Induces Autophagy-Mediated Cell Death in Multiple Myeloma Cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025820"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.bbrc.2013.11.081","article-title":"Induction of Oxiapoptophagy, a Mixed Mode of Cell Death Associated with Oxidative Stress, Apoptosis and Autophagy, on 7-Ketocholesterol-Treated 158N Murine Oligodendrocytes: Impairment by \u03b1-Tocopherol","volume":"446","author":"Nury","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/aps.2013.5","article-title":"Application and Interpretation of Current Autophagy Inhibitors and Activators","volume":"34","author":"Yang","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nrc.2017.53","article-title":"Targeting Autophagy in Cancer","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"80770","DOI":"10.18632\/oncotarget.20415","article-title":"PP2A Mediates Apoptosis or Autophagic Cell Death in Multiple Myeloma Cell Lines","volume":"8","author":"Zhou","year":"2017","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"61093","DOI":"10.18632\/oncotarget.17862","article-title":"Endoplasmic Reticulum Stress Induces Autophagy and Apoptosis While Inhibiting Proliferation and Drug Resistance in Multiple Myeloma through the PI3K\/Akt\/MTOR Signaling Pathway","volume":"8","author":"Fu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.ejmech.2017.12.039","article-title":"Natural Compounds and Combination Therapy in Colorectal Cancer Treatment","volume":"144","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1080\/17512433.2020.1738218","article-title":"Cancer Prevention and Treatment Using Combination Therapy with Natural Compounds","volume":"13","author":"Sauter","year":"2020","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13520","DOI":"10.1073\/pnas.1002922107","article-title":"Identification and Pharmacological Characterization of Cholesterol-5,6-Epoxide Hydrolase as a Target for Tamoxifen and AEBS Ligands","volume":"107","author":"Paillasse","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00277-007-0375-6","article-title":"Cholesterol Levels in Patients with Multiple Myeloma","volume":"87","author":"Yavasoglu","year":"2008","journal-title":"Ann. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.plipres.2008.04.002","article-title":"Sterol Regulators of Cholesterol Homeostasis and beyond: The Oxysterol Hypothesis Revisited and Revised","volume":"47","author":"Gill","year":"2008","journal-title":"Prog. Lipid Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/S0006-291X(03)00412-1","article-title":"Impairment of the Cytotoxic and Oxidative Activities of 7\u03b2-Hydroxycholesterol and 7-Ketocholesterol by Esterification with Oleate","volume":"303","author":"Monier","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3747\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:34:57Z","timestamp":1760164497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/15\/3747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,26]]},"references-count":41,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["cancers13153747"],"URL":"https:\/\/doi.org\/10.3390\/cancers13153747","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,26]]}}}