Unveiling the Anticancer Effects of SGLT-2i: Mechanisms and Therapeutic Potential

Overview

Journal Front Pharmacol

Date 2024 Apr 10

PMID 38595915

Authors

Min Sun

Jilei Sun

Wei Sun

Xiaonan Li

Zhe Wang

Liwei Sun

Yuehui Wang

Affiliations

Soon will be listed here.

Abstract

Cancer and diabetes are significant diseases that pose a threat to human health. Their interconnection is complex, particularly when they coexist, often necessitating multiple therapeutic approaches to attain remission. Sodium-glucose cotransporter protein two inhibitors (SGLT-2i) emerged as a treatment for hyperglycemia, but subsequently exhibited noteworthy extra-glycemic properties, such as being registered for the treatment of heart failure and chronic kidney disease, especially with co-existing albuminuria, prompting its assessment as a potential treatment for various non-metabolic diseases. Considering its overall tolerability and established use in diabetes management, SGLT-2i may be a promising candidate for cancer therapy and as a supplementary component to conventional treatments. This narrative review aimed to examine the potential roles and mechanisms of SGLT-2i in the management of diverse types of cancer. Future investigations should focus on elucidating the antitumor efficacy of individual SGLT-2i in different cancer types and exploring the underlying mechanisms. Additionally, clinical trials to evaluate the safety and feasibility of incorporating SGLT-2i into the treatment regimen of specific cancer patients and determining appropriate dosage combinations with established antitumor agents would be of significant interest.

Citing Articles

Doxorubicin-induced cardiometabolic disturbances: what can we do?.

Avagimyan A, Pogosova N, Rizzo M, Sarrafzadegan N Front Clin Diabetes Healthc. 2025; 6:1537699.

PMID: 40027901 PMC: 11868090. DOI: 10.3389/fcdhc.2025.1537699.

Exploring the Role of SGLT2 Inhibitors in Cancer: Mechanisms of Action and Therapeutic Opportunities.

Pandey A, Alcaraz Jr M, Saggese P, Soto A, Gomez E, Jaldu S Cancers (Basel). 2025; 17(3).

PMID: 39941833 PMC: 11815934. DOI: 10.3390/cancers17030466.

Anti-Diabetic Therapies and Cancer: From Bench to Bedside.

Kounatidis D, Vallianou N, Karampela I, Rebelos E, Kouveletsou M, Dalopoulos V Biomolecules. 2024; 14(11).

PMID: 39595655 PMC: 11591849. DOI: 10.3390/biom14111479.

Obesity-Associated Colorectal Cancer.

Gonzalez-Gutierrez L, Motino O, Barriuso D, de la Puente-Aldea J, Alvarez-Frutos L, Kroemer G Int J Mol Sci. 2024; 25(16).

PMID: 39201522 PMC: 11354800. DOI: 10.3390/ijms25168836.

Effect of Jardiance on glucose uptake into astrocytomas.

Ghezzi C, Ellingson B, Lai A, Liu J, Barrio J, Wright E J Neurooncol. 2024; 169(2):437-444.

PMID: 39037688 PMC: 11341586. DOI: 10.1007/s11060-024-04746-8.

References

Si W, Zhou J, Zhao Y, Zheng J, Cui L . SET7/9 promotes multiple malignant processes in breast cancer development via RUNX2 activation and is negatively regulated by TRIM21. Cell Death Dis. 2020; 11(2):151. PMC: 7044199. DOI: 10.1038/s41419-020-2350-2. View

Liyanage T, Ninomiya T, Jha V, Neal B, Patrice H, Okpechi I . Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015; 385(9981):1975-82. DOI: 10.1016/S0140-6736(14)61601-9. View

Liu G, Zhu J, Yu M, Cai C, Zhou Y, Yu M . Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients. J Transl Med. 2015; 13:144. PMC: 4490642. DOI: 10.1186/s12967-015-0500-6. View

Okada J, Yamada E, Saito T, Yokoo H, Osaki A, Shimoda Y . Dapagliflozin Inhibits Cell Adhesion to Collagen I and IV and Increases Ectodomain Proteolytic Cleavage of DDR1 by Increasing ADAM10 Activity. Molecules. 2020; 25(3). PMC: 7038111. DOI: 10.3390/molecules25030495. View

Chung C, Lakhani I, Chou O, Lee T, Dee E, Ng K . Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in Type 2 diabetes mellitus: A population-based study. Cancer Med. 2023; 12(11):12299-12315. PMC: 10278500. DOI: 10.1002/cam4.5927. View

Komatsu S, Nomiyama T, Numata T, Kawanami T, Hamaguchi Y, Iwaya C . SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation. Endocr J. 2019; 67(1):99-106. DOI: 10.1507/endocrj.EJ19-0428. View

Saito T, Okada S, Yamada E, Shimoda Y, Osaki A, Tagaya Y . Effect of dapagliflozin on colon cancer cell [Rapid Communication]. Endocr J. 2015; 62(12):1133-7. DOI: 10.1507/endocrj.EJ15-0396. View

Obermeier M, Yao M, Khanna A, Koplowitz B, Zhu M, Li W . In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos. 2009; 38(3):405-14. DOI: 10.1124/dmd.109.029165. View

Murakami K, Sasaki Y, Asahiyama M, Yano W, Takizawa T, Kamiya W . Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells. 2022; 11(4). PMC: 8870369. DOI: 10.3390/cells11040720. View

10.

Yamamoto T, Seino Y, Fukumoto H, Koh G, Yano H, Inagaki N . Over-expression of facilitative glucose transporter genes in human cancer. Biochem Biophys Res Commun. 1990; 170(1):223-30. DOI: 10.1016/0006-291x(90)91263-r. View

11.

Lee S, Jeon H, Ju M, Kim C, Yoon G, Han S . Wnt/Snail signaling regulates cytochrome C oxidase and glucose metabolism. Cancer Res. 2012; 72(14):3607-17. DOI: 10.1158/0008-5472.CAN-12-0006. View

12.

Steinberg G, Carling D . AMP-activated protein kinase: the current landscape for drug development. Nat Rev Drug Discov. 2019; 18(7):527-551. DOI: 10.1038/s41573-019-0019-2. View

13.

Barron C, Bilan P, Tsakiridis T, Tsiani E . Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism. 2016; 65(2):124-39. DOI: 10.1016/j.metabol.2015.10.007. View

14.

Luo J, Hendryx M, Dong Y . Sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-small cell lung cancer survival. Br J Cancer. 2023; 128(8):1541-1547. PMC: 10070339. DOI: 10.1038/s41416-023-02177-2. View

15.

Lai J, Fu Y, Tian S, Huang S, Luo X, Lin L . Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice. Mol Ther. 2021; 29(5):1758-1771. PMC: 8116609. DOI: 10.1016/j.ymthe.2021.02.005. View

16.

Hsu P, Sabatini D . Cancer cell metabolism: Warburg and beyond. Cell. 2008; 134(5):703-7. DOI: 10.1016/j.cell.2008.08.021. View

17.

Takahashi H, Kessoku T, Kawanaka M, Nonaka M, Hyogo H, Fujii H . Ipragliflozin Improves the Hepatic Outcomes of Patients With Diabetes with NAFLD. Hepatol Commun. 2021; 6(1):120-132. PMC: 8710792. DOI: 10.1002/hep4.1696. View

18.

Vrhovac Madunic I, Breljak D, Karaica D, Koepsell H, Sabolic I . Expression profiling and immunolocalization of Na-D-glucose-cotransporter 1 in mice employing knockout mice as specificity control indicate novel locations and differences between mice and rats. Pflugers Arch. 2017; 469(12):1545-1565. PMC: 5691098. DOI: 10.1007/s00424-017-2056-1. View

19.

Shibata T, Aburatani H . Exploration of liver cancer genomes. Nat Rev Gastroenterol Hepatol. 2014; 11(6):340-9. DOI: 10.1038/nrgastro.2014.6. View

20.

Wright E . Glucose transport families SLC5 and SLC50. Mol Aspects Med. 2013; 34(2-3):183-96. DOI: 10.1016/j.mam.2012.11.002. View