{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T09:58:07Z","timestamp":1771235887154,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Norte Portugal Regional Operational Programme (NORTE 2020)","award":["NORTE-01-0145-FEDER-000055"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000055"]}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["projects UIDB\/50026\/2020 and UIDP\/50026\/2020, fellowship SFRH\/BPD\/116784\/2016"],"award-info":[{"award-number":["projects UIDB\/50026\/2020 and UIDP\/50026\/2020, fellowship SFRH\/BPD\/116784\/2016"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords \u201cAZD3965 in vivo\u201d as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response.<\/jats:p>","DOI":"10.3390\/molecules27010181","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["In Vivo Anticancer Activity of AZD3965: A Systematic Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Ana","family":"Silva","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Beatriz","family":"Antunes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"given":"Alberta","family":"Batista","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-6489","authenticated-orcid":false,"given":"Filipa","family":"Pinto-Ribeiro","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1770-4544","authenticated-orcid":false,"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-3752","authenticated-orcid":false,"given":"Julieta","family":"Afonso","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"},{"name":"ICVS\/3Bs-PT Government Associate Laboratory, 4805-017 Guimar\u00e3es, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.cell.2008.08.021","article-title":"Cancer cell metabolism: Warburg and beyond","volume":"134","author":"Hsu","year":"2008","journal-title":"Cell"},{"key":"ref_2","first-page":"119","article-title":"Reexamining cancer metabolism: Lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect","volume":"38","author":"Brooks","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1146\/annurev-cancerbio-030419-033556","article-title":"Lactate and Acidity in the Cancer Microenvironment","volume":"4","author":"Parks","year":"2020","journal-title":"Annu. Rev. Cancer Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.molmet.2019.07.006","article-title":"Monocarboxylate transporters in cancer","volume":"33","author":"Payen","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Miranda-Goncalves, V., Goncalves, C.S., Granja, S., Vieira de Castro, J., Reis, R.M., Costa, B.M., and Baltazar, F. (2021). MCT1 Is a New Prognostic Biomarker and Its Therapeutic Inhibition Boosts Response to Temozolomide in Human Glioblastoma. Cancers, 13.","DOI":"10.3390\/cancers13143468"},{"key":"ref_6","unstructured":"US National Library of Medicine (2021, May 30). ClinicalTrials.gov, Available online: https:\/\/www.clinicaltrials.gov\/ct2\/show\/NCT01791595?term=AZD3965&cond=cancer&draw=2&rank=1."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1158\/1078-0432.CCR-04-2626","article-title":"Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development","volume":"11","author":"Kelloff","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.yexmp.2010.08.006","article-title":"Cancer metabolism: The Warburg effect today","volume":"89","author":"Ferreira","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The Metabolism of Tumors in the Body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/iub.1216","article-title":"Lactate dehydrogenase A in cancer: A promising target for diagnosis and therapy","volume":"65","author":"Miao","year":"2013","journal-title":"IUBMB Life"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrc2981","article-title":"Regulation of cancer cell metabolism","volume":"11","author":"Cairns","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6921","DOI":"10.1158\/0008-5472.CAN-11-1457","article-title":"Lactate: A metabolic key player in cancer","volume":"71","author":"Hirschhaeuser","year":"2011","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1182\/blood-2006-07-035972","article-title":"Inhibitory effect of tumor cell-derived lactic acid on human T cells","volume":"109","author":"Fischer","year":"2007","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3389\/fonc.2020.00231","article-title":"Lactate beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy","volume":"10","author":"Baltazar","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_15","first-page":"453","article-title":"Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release","volume":"39","author":"Goetze","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_16","unstructured":"Serpa, J. (2020). Lactate and Lactate Transporters as Key Players in the Maintenance of the Warburg Effect. Tumor Microenvironment: The Main Driver of Metabolic Adaptation, Springer International Publishing."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.mam.2012.05.003","article-title":"The SLC16 gene family\u2014Structure, role and regulation in health and disease","volume":"34","author":"Halestrap","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112393","DOI":"10.1016\/j.ejmech.2020.112393","article-title":"Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights","volume":"199","author":"Puri","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/s41416-019-0717-x","article-title":"Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration","volume":"122","author":"Wantuch","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1172\/JCI69741","article-title":"Targeting lactate metabolism for cancer therapeutics","volume":"123","author":"Doherty","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3896","DOI":"10.1093\/emboj\/19.15.3896","article-title":"CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression","volume":"19","author":"Kirk","year":"2000","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1038\/onc.2015.360","article-title":"Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters","volume":"35","author":"Gan","year":"2016","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1158\/0008-5472.CAN-11-2474","article-title":"Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors","volume":"72","author":"Boidot","year":"2012","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"945","DOI":"10.3892\/or.2016.4884","article-title":"Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment","volume":"36","author":"Hu","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_25","first-page":"3930","article-title":"Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice","volume":"118","author":"Sonveaux","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1208\/s12248-018-0261-2","article-title":"In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model","volume":"21","author":"Guan","year":"2018","journal-title":"AAPS J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1158\/1078-0432.CCR-13-2270","article-title":"Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer","volume":"20","author":"Polanski","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3324\/haematol.2016.163030","article-title":"Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma","volume":"102","author":"Noble","year":"2017","journal-title":"Haematologica"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41416-020-0727-8","article-title":"A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965","volume":"122","author":"McNeillis","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1200\/JCO.2017.35.15_suppl.2516","article-title":"A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours","volume":"35","author":"Halford","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1200\/JCO.2021.39.15_suppl.3115","article-title":"Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL)","volume":"39","author":"Halford","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1158\/1535-7163.MCT-13-1091","article-title":"Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport","volume":"13","author":"Bola","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69219","DOI":"10.18632\/oncotarget.18215","article-title":"Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt\u2019s lymphoma anti-tumor activity","volume":"8","author":"Curtis","year":"2017","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5913","DOI":"10.1158\/0008-5472.CAN-16-2686","article-title":"MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy","volume":"77","author":"Wantuch","year":"2017","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1158\/1535-7163.MCT-17-1253","article-title":"Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance","volume":"17","author":"Quanz","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Braga, M., Kaliszczak, M., Carroll, L., Schug, Z.T., Heinzmann, K., Baxan, N., Benito, A., Valbuena, G.N., Stribbling, S., and Beckley, A. (2020). Tracing Nutrient Flux Following Monocarboxylate Transporter-1 Inhibition with AZD3965. Cancers, 12.","DOI":"10.3390\/cancers12061703"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/j.celrep.2016.01.057","article-title":"MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4","volume":"14","author":"Hong","year":"2016","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"16804","DOI":"10.1038\/s41598-018-35103-1","article-title":"Statin-induced metabolic reprogramming in head and neck cancer: A biomarker for targeting monocarboxylate transporters","volume":"8","author":"Mehibel","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2018.08.006","article-title":"Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies","volume":"28","author":"Apicella","year":"2018","journal-title":"Cell Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"690796","DOI":"10.3389\/fcell.2021.690796","article-title":"Oncogenic Chromatin Modifier KAT2A Activates MCT1 to Drive the Glycolytic Process and Tumor Progression in Renal Cell Carcinoma","volume":"9","author":"Guo","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin."},{"key":"ref_44","first-page":"27","article-title":"Lactate and cancer: Revisiting the warburg effect in an era of lactate shuttling","volume":"1","author":"Goodwin","year":"2014","journal-title":"Front. Nutr."},{"key":"ref_45","first-page":"676","article-title":"Mechanisms of action of CD20 antibodies","volume":"2","author":"Boross","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nature25003","article-title":"KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase","volume":"552","author":"Wang","year":"2017","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1158\/0008-5472.CAN-13-2034","article-title":"Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis","volume":"74","author":"Doherty","year":"2014","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1158\/0008-5472.CAN-17-0764","article-title":"Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter","volume":"77","author":"Payen","year":"2017","journal-title":"Cancer Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:55:07Z","timestamp":1760169307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/1\/181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,29]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["molecules27010181"],"URL":"https:\/\/doi.org\/10.3390\/molecules27010181","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,29]]}}}