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Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth

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Abstract

Cancer is a major cause of death in patients with diabetes. Incretin therapy has received much attention because of its tissue-protective effects. We have previously reported an anti-breast cancer effect of glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4). An anti-cancer effect of metformin is well recognized. Therefore, we examined the effect of combined treatment with Ex-4 and metformin in breast cancer cells. In human breast cancer cell lines MCF-7, MDA-MB-231, and KPL-1, 0.1–10 mM metformin significantly reduced the cell number in growth curve analysis in a dose-dependent manner. Furthermore, combined treatment with 0.1 mM metformin and 10 nM Ex-4 additively attenuated the growth curve progression of breast cancer cells. In a bromodeoxyuridine (BrdU) assay, Ex-4 or metformin significantly decreased breast cancer cell proliferation and further reduction of BrdU incorporation was observed by combined treatment with Ex-4 and metformin, which suggested that Ex-4 and metformin additively decreased DNA synthesis in breast cancer cells. Although apoptotic cells were not observed among Ex-4-treated breast cancer cells, apoptotic cells were clearly detected among metformin-treated breast cancer cells by apoptosis assays. Furthermore, metformin decreased BCL-2 expression in MCF-7 cells. In vivo experiments using a xenograft model showed that Ex-4 and metformin significantly decreased the breast tumor weight and Ki67-positive proliferative cancer cells, and metformin reduced the serum insulin level in mice. These data suggested that Ex-4 and metformin attenuated cell proliferation and metformin induced apoptosis in breast cancer cells. Combined treatment of Ex-4 and metformin may be an optional therapy to inhibit breast cancer progression.

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Acknowledgements

We thank Mitchell Arico from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Yuki Tanaka, Takako Kawanami, Yuriko Hamaguchi & Daiji Kawanami

  2. Fukuoka Saiseikai Omuta Hospital, 810 Taguma, Omuta, Fukuoka, 814-0174, Japan

    Chikayo Iwaya

  3. Okabe Hospital, 1-2-1 Myoujinzaka, Umimachi, Kasuya-gun, Fukuoka, 811-2122, Japan

    Tsuyoshi Horikawa

  4. Terasawa Hospital, 1-14-11 Ichizaki, Minami-ku, Fukuoka, 815-0084, Japan

    Toru Shigeoka

  5. Muta Hospital, 3-9-1 Hoshikuma, Sawara-ku, Fukuoka, 814-0163, Japan

    Toshihiko Yanase

  6. Department of Diabetes, Metabolism and Endocrinology, International University of Health and Welfare Ichikawa Hospital, 6-1-14 Kounodai, Ichikawa, Chiba, 272-0827, Japan

    Takashi Nomiyama

  7. Department of Diabetes, Metabolism and Endocrinology, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba, 286-8686, Japan

    Takashi Nomiyama

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  1. Yuki Tanaka
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  9. Takashi Nomiyama
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Contributions

YT, CI, TK, and YH performed experiments and data analysis. TH, TS, TY, and DK reviewed the manuscript. TN wrote the manuscript and conceived the research hypothesis and design.

Corresponding author

Correspondence to Takashi Nomiyama.

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Conflict of interest

T.N. received lecture fees from Sumitomo Dainippon Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Nihon Eli Lilly. D.K. received lecture fees from Ono Pharmaceutical, Novo Nordisc Pharma, MSD, Sanofi K.K., and Takeda Pharmaceutical, and research grants from Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Sumitomo Dainippon Pharma, and Ono Pharmaceutical. The other authors declare that they have no conflicts of interest.

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Tanaka, Y., Iwaya, C., Kawanami, T. et al. Combined treatment with glucagon-like peptide-1 receptor agonist exendin-4 and metformin attenuates breast cancer growth. Diabetol Int 13, 480–492 (2022). https://doi.org/10.1007/s13340-021-00560-z

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