{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T02:56:17Z","timestamp":1773975377764,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T00:00:00Z","timestamp":1726272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT","award":["PTDC\/SAUNUT\/2165\/2021"],"award-info":[{"award-number":["PTDC\/SAUNUT\/2165\/2021"]}]},{"name":"FCT","award":["CEECIND\/08492\/2022"],"award-info":[{"award-number":["CEECIND\/08492\/2022"]}]},{"name":"FCT","award":["PTDC\/SAUNUT\/2165\/2021"],"award-info":[{"award-number":["PTDC\/SAUNUT\/2165\/2021"]}]},{"name":"FCT","award":["CEECIND\/08492\/2022"],"award-info":[{"award-number":["CEECIND\/08492\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism.<\/jats:p>","DOI":"10.3390\/ijms25189932","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T01:52:31Z","timestamp":1726624351000},"page":"9932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of Sodium-Glucose Co-Transporter 2 Inhibitors Combined with Metformin on Pancreatic Cancer Cell Lines"],"prefix":"10.3390","volume":"25","author":[{"given":"Andr\u00e9","family":"Cristov\u00e3o","sequence":"first","affiliation":[{"name":"Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-8599","authenticated-orcid":false,"given":"Nelson","family":"Andrade","sequence":"additional","affiliation":[{"name":"Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal"},{"name":"REQUIMTE\/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0525-3416","authenticated-orcid":false,"given":"F\u00e1tima","family":"Martel","sequence":"additional","affiliation":[{"name":"Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal"},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (I3S), University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2937-974X","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Silva","sequence":"additional","affiliation":[{"name":"Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319 Porto, Portugal"},{"name":"REQUIMTE\/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2021.06.027","article-title":"Advances in the epidemiology of pancreatic cancer: Trends, risk factors, screening, and prognosis","volume":"520","author":"Cai","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1533033820962117","DOI":"10.1177\/1533033820962117","article-title":"Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment","volume":"19","author":"Zhao","year":"2020","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.canlet.2016.07.022","article-title":"Modifiable and non-modifiable risk factors for pancreatic cancer: A review","volume":"381","author":"Midha","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4846","DOI":"10.3748\/wjg.v24.i43.4846","article-title":"Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes","volume":"24","author":"McGuigan","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1210\/en.2018-00574","article-title":"Diabetes, Obesity, and Breast Cancer","volume":"159","author":"Kang","year":"2018","journal-title":"Endocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1097\/MPA.0000000000001168","article-title":"Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer","volume":"47","author":"Hart","year":"2018","journal-title":"Pancreas"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1186\/s12935-022-02803-8","article-title":"Landmarks in pancreatic cancer studies","volume":"22","author":"Xu","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1001\/jama.2019.3805","article-title":"Metformin in 2019","volume":"321","author":"Flory","year":"2019","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/biof.1947","article-title":"Metformin and thymoquinone co-treatment enhance 5-fluorouracil cytotoxicity by suppressing the PI3K\/mTOR\/HIF1alpha pathway and increasing oxidative stress in colon cancer cells","volume":"49","author":"Farrash","year":"2023","journal-title":"Biofactors"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and Molecular Mechanisms of Metformin Action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on mechanisms of action and repurposing potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s10555-021-09977-z","article-title":"Metformin: Review of epidemiology and mechanisms of action in pancreatic cancer","volume":"40","author":"Eibl","year":"2021","journal-title":"Cancer Metastasis Rev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fonseca-Correa, J.I., and Correa-Rotter, R. (2021). Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Front. Med., 8.","DOI":"10.3389\/fmed.2021.777861"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.34067\/KID.0002772021","article-title":"SGLT2 Inhibitors: Physiology and Pharmacology","volume":"2","author":"Wright","year":"2021","journal-title":"Kidney360"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E4111","DOI":"10.1073\/pnas.1511698112","article-title":"Functional expression of sodium-glucose transporters in cancer","volume":"112","author":"Scafoglio","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.canlet.2021.07.035","article-title":"SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis","volume":"519","author":"Ren","year":"2021","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.semcancer.2020.04.006","article-title":"Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics","volume":"68","author":"Kirtonia","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.phrs.2017.07.013","article-title":"Drug repurposing in cancer","volume":"124","author":"Sleire","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"172784","DOI":"10.1016\/j.ejphar.2019.172784","article-title":"Old wine in new bottles: Drug repurposing in oncology","volume":"866","author":"Antoszczak","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s13300-016-0201-z","article-title":"Canagliflozin: Efficacy and Safety in Combination with Metformin Alone or with Other Antihyperglycemic Agents in Type 2 Diabetes","volume":"7","author":"Qiu","year":"2016","journal-title":"Diabetes Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1080\/00325481.2015.1085293","article-title":"Use of oral combination therapy for type 2 diabetes in primary care: Meeting individualized patient goals","volume":"127","author":"Lavernia","year":"2015","journal-title":"Postgrad. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12933-015-0297-x","article-title":"Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus","volume":"14","author":"Fioretto","year":"2015","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Martin, D., Alberti, P., Wigmore, S.J., Demartines, N., and Joliat, G.R. (2023). Pancreatic Cancer Surgery: What Matters to Patients?. J. Clin. Med., 12.","DOI":"10.3390\/jcm12144611"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhou, X., Hu, K., Bailey, P., Springfeld, C., Roth, S., Kurilov, R., Brors, B., Gress, T., Buchholz, M., and An, J. (2021). Clinical Impact of Molecular Subtyping of Pancreatic Cancer. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.743908"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.2217\/imt-2022-0046","article-title":"The poorly immunogenic tumor microenvironment of pancreatic cancer: The impact of radiation therapy, and strategies targeting resistance","volume":"14","author":"Hughes","year":"2022","journal-title":"Immunotherapy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug repositioning: A brief overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-030-65768-0_1","article-title":"Glucose Metabolism in Cancer: The Warburg Effect and Beyond","volume":"1311","author":"Bose","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does it Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1111\/imj.15846","article-title":"The relationship between pancreatic cancer and type 2 diabetes: The Fremantle Diabetes Study Phase I","volume":"52","author":"Davis","year":"2022","journal-title":"Intern. Med. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"170","DOI":"10.5604\/01.3001.0010.3801","article-title":"Metformin\u2014Its potential anti-cancer and anti-aging effects","volume":"71","author":"Podhorecka","year":"2017","journal-title":"Postep. Hig. Med. Dosw."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Basak, D., Gamez, D., and Deb, S. (2023). SGLT2 Inhibitors as Potential Anticancer Agents. Biomedicines, 11.","DOI":"10.3390\/biomedicines11071867"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Navarro, C., Ortega, A., Santeliz, R., Garrido, B., Chacin, M., Galban, N., Vera, I., De Sanctis, J.B., and Bermudez, V. (2022). Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061303"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3892\/ol.2016.4586","article-title":"Expression and clinical significance of glucose transporter-1 in pancreatic cancer","volume":"12","author":"Lu","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20200810","DOI":"10.1259\/bjr.20200810","article-title":"Effect of metformin on (18)F-fluorodeoxyglucose uptake and positron emission tomographic imaging","volume":"95","author":"Zhang","year":"2022","journal-title":"Br. J. Radiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.biopha.2018.03.008","article-title":"Effect of metformin on estrogen and progesterone receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells","volume":"102","author":"Amaral","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.18433\/jpps32879","article-title":"Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy","volume":"25","author":"Bardaweel","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_39","first-page":"4885","article-title":"Mechanisms of metformin inhibiting cancer invasion and migration","volume":"12","author":"Chen","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1007\/s00210-024-03021-x","article-title":"Exploring the therapeutic potential of SGLT2 inhibitors in cancer treatment: Integrating in silico and in vitro investigations","volume":"397","author":"Mohite","year":"2024","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.21873\/anticanres.13933","article-title":"Metformin Inhibits Proliferation and Tumor Growth of QGP-1 Pancreatic Neuroendocrine Tumor Cells by Inducing Cell Cycle Arrest and Apoptosis","volume":"40","author":"Yamana","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Szymczak-Pajor, I., Drzewoski, J., Swiderska, E., Strycharz, J., Gabryanczyk, A., Kasznicki, J., Bogdanska, M., and Sliwinska, A. (2023). Metformin Induces Apoptosis in Human Pancreatic Cancer (PC) Cells Accompanied by Changes in the Levels of Histone Acetyltransferases (Particularly, p300\/CBP-Associated Factor (PCAF) Protein Levels). Pharmaceuticals, 16.","DOI":"10.3390\/ph16010115"},{"key":"ref_43","first-page":"5336","article-title":"Metformin reduces pancreatic cancer cell proliferation and increases apoptosis through MTOR signaling pathway and its dose-effect relationship","volume":"24","author":"Zhao","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dutka, M., Bobinski, R., Francuz, T., Garczorz, W., Zimmer, K., Ilczak, T., Cwiertnia, M., and Hajduga, M.B. (2022). SGLT-2 Inhibitors in Cancer Treatment-Mechanisms of Action and Emerging New Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14235811"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"FSO410","DOI":"10.2144\/fsoa-2019-0053","article-title":"Anticancer activity of metformin: A systematic review of the literature","volume":"5","author":"Aljofan","year":"2019","journal-title":"Future Sci. OA"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yue, J., and Lopez, J.M. (2020). Understanding MAPK Signaling Pathways in Apoptosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072346"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41392-021-00828-5","article-title":"Targeting PI3K\/Akt signal transduction for cancer therapy","volume":"6","author":"He","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.4103\/jcrt.JCRT_963_19","article-title":"Canagliflozin, a SGLT-2 inhibitor, relieves ER stress, modulates autophagy and induces apoptosis in irradiated HepG2 cells: Signal transduction between PI3K\/AKT\/GSK-3beta\/mTOR and Wnt\/beta-catenin pathways; in vitro","volume":"17","author":"Thabet","year":"2021","journal-title":"J. Cancer Res. Ther."},{"key":"ref_49","first-page":"1223","article-title":"Inhibitory effects of canagliflozin on pancreatic cancer are mediated via the downregulation of glucose transporter-1 and lactate dehydrogenase A","volume":"57","author":"Xu","year":"2020","journal-title":"Int. J. Oncol."},{"key":"ref_50","first-page":"89","article-title":"Characterization of the tumorigenic and metastatic properties of a human pancreatic tumor cell line (AsPC-1) implanted orthotopically into nude mice","volume":"6","author":"Tan","year":"1985","journal-title":"Tumour Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/BF02796382","article-title":"Human pancreatic adenocarcinoma: In vitro and in vivo morphology of a new tumor line established from ascites","volume":"18","author":"Chen","year":"1982","journal-title":"In Vitro"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1002\/ijc.2910150505","article-title":"Establishment of a continuous tumor-cell line (panc-1) from a human carcinoma of the exocrine pancreas","volume":"15","author":"Lieber","year":"1975","journal-title":"Int. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9932\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:56:25Z","timestamp":1760111785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,14]]},"references-count":53,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25189932"],"URL":"https:\/\/doi.org\/10.3390\/ijms25189932","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,14]]}}}