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Repurposing sodium-glucose co-transporter 2 inhibitors (SGLT2i) for cancer treatment – A Review

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Abstract

Developed as an antidiabetic drug, recent evidence suggests that several sodium-glucose co-transporter 2 inhibitors (SGLT2i), especially canagliflozin and dapagliflozin, may exhibit in vitro and in vivo anticancer activities in selected cancer types, including an inhibition of tumor growth and induction of cell death. When used in combination with chemotherapy or radiotherapy, SGLT2i may offer possible synergistic effects in enhancing their treatment efficacy while alleviating associated side effects. Potential mechanisms include a reduction of glucose uptake into cancer cells, systemic glucose restriction, modulation of multiple signaling pathways, and regulation of different gene and protein expression. Furthermore, preliminary clinical findings have reported potential anticancer properties of canagliflozin and dapagliflozin in patients with liver and colon cancers respectively, with reference to decreases in their tumor marker levels. Given its general tolerability and routine use in diabetes management, SGLT2i may be a good candidate for drug repurposing in cancer treatment and as adjunct to conventional therapies. While current evidence reveals that only certain SGLT2i appear to be effective against selected cancer types, further studies are needed to explore the antitumor abilities of each SGLT2i in various cancers. Moreover, clinical trials are called for to evaluate the safety and feasibility of introducing SGLT2i in the treatment regimen of patients with specific cancers, and to identify the preferred route of drug administration for targeted delivery to selected tumor sites.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Abbreviations

AFP:

α-Fetoprotein

AMPK:

AMP-activated protein kinase

ATP:

Adenosine triphosphate

CEA:

Carcinoembryonic antigen

CVD:

Cardiovascular diseases

EGFR:

Epidermal growth factor receptor

FOXA1:

Forkhead Box A1

GLUT1:

Glucose transporter 1

HCC:

Hepatocellular carcinoma

LKB1:

Liver kinase B1

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

Me4FDG:

α-Methyl-4[18F]-4-deoxy-D-glucopyranose

mTOR:

Mammalian target of rapamycin

NSCLC:

Non-small cell lung cancer

PET:

Positron emission tomography

SGLT1:

Sodium-glucose co-transporter 1

SGLT2:

Sodium-glucose co-transporter 2

SGLT2i:

Sodium-glucose co-transporter 2 inhibitors

SHH:

Sonic Hedgehog

TNBC:

Triple-negative breast cancer

T2D:

Type 2 diabetes

UGT1A9:

UDP-glucuronosyltransferase 1–9

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Acknowledgements

We thank Mr Matthew Chung for the design and preparation of chord diagrams (Figures 2 and 3), and Ms Xi Xiong for her critical comments to this review.

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Authors and Affiliations

  1. Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Kristy T. K. Lau & Carlos K. H. Wong

  2. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Lui Ng

  3. School of Biomedical Sciences, Faculty of Medicine, Li Ka Shing, The University of Hong Kong, Hong Kong SAR, China

    Jason W. H. Wong

  4. Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

    Herbert H. F. Loong

  5. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Wendy W. L. Chan

  6. Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Chi Ho Lee

  7. Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Carlos K. H. Wong

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Contributions

CKHW had the original idea, reviewed the literature, and contributed to the development of this review. KTKL reviewed the literature and wrote the first draft. LN, JWHW, HHFL, WWLC, and PCHL provided critical input to the content of this review. All authors contributed to the critical review and revision of the manuscript, and approved the final manuscript as submitted.

Corresponding author

Correspondence to Carlos K. H. Wong.

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Conflicts of interest

KTK Lau, L Ng, and PCH Lee have no conflict of interest to declare. JWH Wong received research funding from the Hong Kong Research Grants Council, outside the submitted work. HHF Loong received personal fees from Novartis, personal fees from Pfizer, grants and personal fees from MSD, personal fees from Eisai, personal fees from Boehringer-Ingelheim, and grants from Mundipharma, outside the submitted work. WWL Chan received research funding from the Pfizer, outside the submitted work. CKH Wong received research funding from the EuroQoL Group Research Foundation, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund, outside the submitted work.

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Lau, K.T.K., Ng, L., Wong, J.W.H. et al. Repurposing sodium-glucose co-transporter 2 inhibitors (SGLT2i) for cancer treatment – A Review. Rev Endocr Metab Disord 22, 1121–1136 (2021). https://doi.org/10.1007/s11154-021-09675-9

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