{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:39:03Z","timestamp":1760146743096,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French National Cancer Institut","award":["INCa\u20142022-037","U01CA289226"],"award-info":[{"award-number":["INCa\u20142022-037","U01CA289226"]}]},{"name":"National Cancer Institute of the National Institutes of Health","award":["INCa\u20142022-037","U01CA289226"],"award-info":[{"award-number":["INCa\u20142022-037","U01CA289226"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, pancreas, and pharynx. This poses the question of a potential pro-cancer effect of pharmaceutical opioid analgesics. In vitro studies employing a variety of experimental conditions suggest that opioid alkaloids have proliferative or antiproliferative effects. We set out to reconcile this discrepancy and explore the hypothesis that opioids promote cancer cell proliferation in an organ-dependent fashion. Methods: Using strictly controlled conditions, we tested the effect of morphine on the proliferation of a series of human cancer cell lines isolated from organs where cancer risk was linked causally to opium consumption in human studies (i.e., lung, bladder, and larynx), or control organs where no link between cancer risk and opium consumption has been reported in human studies (i.e., breast, colon, prostate). Results: Our results showed a minimal effect on proliferation on any cell line and no trend supporting an organ-specific effect of morphine. Conclusions: This argues against a direct effect of opioids on tumour cell proliferation to support their organ-specific effect.<\/jats:p>","DOI":"10.3390\/ph17121656","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T06:16:14Z","timestamp":1733724974000},"page":"1656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Comparative Effect of Morphine on Proliferation of Cancer Cell Lines Originating from Different Organs: An In Vitro Study"],"prefix":"10.3390","volume":"17","author":[{"given":"Lydia","family":"Whitham","sequence":"first","affiliation":[{"name":"School of Pharmacy, University of Queensland, Brisbane 4072, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3972-7824","authenticated-orcid":false,"given":"Mahdi","family":"Sheikh","sequence":"additional","affiliation":[{"name":"Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), 69007 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8248-0244","authenticated-orcid":false,"given":"Markus W.","family":"Hollmann","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology, Amsterdam University Medical Center, 1081 Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4895-7381","authenticated-orcid":false,"given":"Marie-Odile","family":"Parat","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Queensland, Brisbane 4072, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Snijders, R.A.H., Brom, L., Theunissen, M., and van den Beuken-van Everdingen, M.H.J. (2023). Update on Prevalence of Pain in Patients with Cancer 2022: A Systematic Literature Review and Meta-Analysis. Cancers, 15.","DOI":"10.3390\/cancers15030591"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/jncimonographs\/lgh015","article-title":"Occurrence of cancer pain","volume":"2004","author":"McGuire","year":"2004","journal-title":"J. Natl. Cancer Inst. Monogr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"286","DOI":"10.3322\/caac.21823","article-title":"Opioid analgesics for nociceptive cancer pain: A comprehensive review","volume":"74","author":"Hayes","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1016\/S0140-6736(21)00393-7","article-title":"Chronic pain: An update on burden, best practices, and new advances","volume":"397","author":"Cohen","year":"2021","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1111\/joim.13026","article-title":"What proportion of patients with chronic noncancer pain are prescribed an opioid medicine? Systematic review and meta-regression of observational studies","volume":"287","author":"Mathieson","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1213\/ANE.0000000000001293","article-title":"Morphine Suppresses Lung Cancer Cell Proliferation Through the Interaction with Opioid Growth Factor Receptor: An In Vitro and Human Lung Tissue Study","volume":"123","author":"Kim","year":"2016","journal-title":"Anesth. Analg."},{"key":"ref_7","first-page":"441","article-title":"Morphine promotes migration and lung metastasis of mouse melanoma cells","volume":"73","author":"Vaseghi","year":"2023","journal-title":"Braz. J. Anesthesiol. (Engl. Ed.)"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0304-3835(02)00360-9","article-title":"Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells","volume":"187","author":"Harimaya","year":"2002","journal-title":"Cancer Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1248\/bpb.16.762","article-title":"Enhancement of tumor growth by morphine and its possible mechanism in mice","volume":"16","author":"Ishikawa","year":"1993","journal-title":"Biol. Pharm. Bull."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1001\/archsurg.1991.01410280056007","article-title":"Effect of morphine on growth of metastatic colon cancer in vivo","volume":"126","author":"Yeager","year":"1991","journal-title":"Arch. Surg"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"984","DOI":"10.2353\/ajpath.2010.090621","article-title":"Morphine suppresses tumor angiogenesis through a HIF-1\u03b1\/p38MAPK pathway","volume":"177","author":"Koodie","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0014-2999(02)01450-4","article-title":"Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation","volume":"441","author":"Sasamura","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3892\/etm.2016.3346","article-title":"Comparison of oxycodone and morphine on the proliferation, apoptosis and expression of related molecules in the A549 human lung adenocarcinoma cell line","volume":"12","author":"Tian","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_14","first-page":"857","article-title":"Induction of apoptosis by morphine in human tumor cell lines","volume":"27","author":"Hatsukari","year":"2007","journal-title":"Anticancer. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/bja\/aeu090","article-title":"Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer","volume":"113","author":"Nguyen","year":"2014","journal-title":"Br. J. Anaesth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.bbadis.2014.01.003","article-title":"Morphine modulates cell proliferation through mir133b & mir128 in the neuroblastoma SH-SY5Y cell line","volume":"1842","year":"2014","journal-title":"Bba-Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1186\/s12935-021-02334-8","article-title":"Morphine promotes the malignant biological behavior of non-small cell lung cancer cells through the MOR\/Src\/mTOR pathway","volume":"21","author":"Liu","year":"2021","journal-title":"Cancer Cell Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.31768\/2312-8852.2018.40(3):190-193","article-title":"The impact of morphine treatment on bladder cancer cell proliferation and apoptosis: In vitro studies","volume":"40","author":"Harper","year":"2018","journal-title":"Exp. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Levi, L., Hikri, E., Popovtzer, A., Dayan, A., Levi, A., Bachar, G., Mizrachi, A., and Shoffel-Havakuk, H. (2023). Effect of Opioid Receptor Activation and Blockage on the Progression and Response to Treatment of Head and Neck Squamous Cell Carcinoma. J. Clin. Med., 12.","DOI":"10.3390\/jcm12041277"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7586100","DOI":"10.1155\/2021\/7586100","article-title":"Sufentanil Inhibits the Proliferation and Metastasis of Esophageal Cancer by Inhibiting the NF-kappaB and Snail Signaling Pathways","volume":"2021","author":"Tang","year":"2021","journal-title":"J. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1248\/bpb.b19-00779","article-title":"Morphine Stimulates Migration and Growth and Alleviates the Effects of Chemo Drugs via AMPK-Dependent Induction of Epithelial-Mesenchymal Transition in Esophageal Carcinoma Cells","volume":"43","author":"Zhang","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1093\/carcin\/17.11.2337","article-title":"Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression","volume":"17","author":"Sueoka","year":"1996","journal-title":"Carcinogenesis"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yu, Y., Li, D., Duan, J., Xu, H., Li, L., Tan, D., and Yan, H. (2020). The pro- and anti-cancer effects of oxycodone are associated with epithelial growth factor receptor level in cancer cells. Biosci. Rep., 40.","DOI":"10.1042\/BSR20193524"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, Q., Liu, Z., Tang, S., and Wu, Z. (2022). Morphine suppresses the immune function of lung cancer by up-regulating MAEL expression. BMC Pharmacol. Toxicol., 23.","DOI":"10.1186\/s40360-022-00632-z"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"IARC Monographs Vol 126 Group (2020). Carcinogenicity of opium consumption. Lancet Oncol., 21, 1407\u20131408.","DOI":"10.1016\/S1470-2045(20)30611-2"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.1016\/j.jtho.2023.09.132","article-title":"MA03.08 Regular Use of Pharmaceutical Opioids and Subsequent Risk of Lung Cancer","volume":"18","author":"Sheikh","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e401","DOI":"10.1016\/j.bja.2022.12.007","article-title":"Opioid medications: An emerging cancer risk factor?","volume":"130","author":"Sheikh","year":"2023","journal-title":"Br. J. Anaesth."},{"key":"ref_28","unstructured":"IARC Working Group on the Identification of Carcinogenic Hazards to Humans (2021). IARC Monographs on the Identification of Carcinogenic Hazards to Humans. Opium Consum., 126, 1\u2013253."},{"key":"ref_29","first-page":"41","article-title":"Relationship between Plasma Morphine Concentrations and Pharmacologic Effects in Postoperative-Patients Using Patient-Controlled Analgesia","volume":"4","author":"Graves","year":"1985","journal-title":"Clin. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neulet.2013.07.039","article-title":"Differentiation state affects morphine induced cell regulation in neuroblastoma cultured cells","volume":"555","author":"Fiore","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1111\/j.1365-2125.1979.tb01047.x","article-title":"Serum morphine concentration after oral administration of diamorphine hydrochloride and morphine sulphate","volume":"8","author":"Aherne","year":"1979","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_32","first-page":"2413","article-title":"Induction of early apoptosis marker by morphine in human lung and breast carcinoma cell lines","volume":"23","author":"Hatsukari","year":"2003","journal-title":"Anticancer. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1213\/ANE.0b013e31820568af","article-title":"The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation","volume":"112","author":"Mathew","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1213\/ANE.0b013e318232b35a","article-title":"Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer","volume":"113","author":"Fujioka","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_35","first-page":"2234","article-title":"Binding of Opioids to Human MCF-7 Breast Cancer Cells and Their Effects on Growth","volume":"50","author":"Maneckjee","year":"1990","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s00432-022-03945-y","article-title":"D,L-Methadone enhances the cytotoxic activity of standard chemotherapeutic agents on pediatric rhabdomyosarcoma","volume":"148","author":"Urla","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10620-007-9897-y","article-title":"Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon","volume":"53","author":"Nylund","year":"2008","journal-title":"Dig. Dis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"216808","DOI":"10.1016\/j.canlet.2024.216808","article-title":"PCTA, a pan-cancer cell line transcriptome atlas","volume":"588","author":"Cheng","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1248\/bpb.b17-00215","article-title":"Morphine Can Inhibit the Growth of Breast Cancer MCF-7 Cells by Arresting the Cell Cycle and Inducing Apoptosis","volume":"40","author":"Chen","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","article-title":"The tumor microenvironment","volume":"30","author":"Anderson","year":"2020","journal-title":"Curr. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.canlet.2015.07.039","article-title":"Tumor microenvironment: Sanctuary of the devil","volume":"368","author":"Hui","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Oliver, A.J., Lau, P.K.H., Unsworth, A.S., Loi, S., Darcy, P.K., Kershaw, M.H., and Slaney, C.Y. (2018). Tissue-Dependent Tumor Microenvironments and Their impact on immunotherapy Responses. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00070"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Conway, J.W., Braden, J., Wilmott, J.S., Scolyer, R.A., Long, G.V., and Pires da Silva, I. (2022). The effect of organ-specific tumor microenvironments on response patterns to immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1030147"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/bjc.2014.384","article-title":"Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: A systematic literature review","volume":"111","author":"Boland","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S221","DOI":"10.1097\/01.CCM.0000057847.32590.C1","article-title":"Endothelial cell heterogeneity","volume":"31","author":"Aird","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Conway, E.M., and Carmeliet, P. (2004). The diversity of endothelial cells: A challenge for therapeutic angiogenesis. Genome Biol., 5.","DOI":"10.1186\/gb-2004-5-2-207"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2353\/ajpath.2006.050834","article-title":"Vascular endothelial growth factor localization in the adult","volume":"168","author":"Maharaj","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1111\/febs.16660","article-title":"Endothelial cell diversity: The many facets of the crystal","volume":"291","author":"Li","year":"2024","journal-title":"Febs. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"104694","DOI":"10.1016\/j.mvr.2024.104694","article-title":"Modulation of angiopoietin-2 and Tie2: Organ specific effects of microvascular leakage and edema in mice","volume":"154","author":"Dekker","year":"2024","journal-title":"Microvasc. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.neo.2015.08.002","article-title":"EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation","volume":"17","author":"Minder","year":"2015","journal-title":"Neoplasia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/cac2.12005","article-title":"Spectrum of EGFR aberrations and potential clinical implications: Insights from integrative pan-cancer analysis","volume":"40","author":"Liu","year":"2020","journal-title":"Cancer Commun."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Lennon, F.E., Mirzapoiazova, T., Mambetsariev, B., Poroyko, V.A., Salgia, R., Moss, J., and Singleton, P.A. (2014). The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091577"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1656\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:50:26Z","timestamp":1760115026000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1656"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,9]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ph17121656"],"URL":"https:\/\/doi.org\/10.3390\/ph17121656","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2024,12,9]]}}}