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Sodium-glucose cotransporter 2 inhibitor canagliflozin attenuates lung cancer cell proliferation in vitro

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Abstract

Cancer is a major cause of death in patients with type 2 diabetes mellitus (T2DM) and lung cancer is one of the most prevalent cancers in patients with T2DM. In the present study, we examined the anti-cancer effect of the Sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, using a lung cancer model. In lung cancer tissues from non-T2DM human subjects, SGLT2 was detected by immunohistochemistry. SGLT2 mRNA and protein were also detected in A549, H1975 and H520 lung cancer cell lines by RT-PCR and immunohistochemistry, respectively. Canagliflozin at 1–50 µM significantly suppressed the growth of A549 cells in a dose-dependent manner. In BrdU assays, canagliflozin attenuated the proliferation of A549 cells, but did not induce apoptosis. In cell cycle analysis, S phase entry was attenuated by canagliflozin in A549 cells. In in vivo experiments, a xenograft model of athymic mice implanted with A549 lung cancer cells was treated with low and high dose oral canagliflozin. Despite the results of the in vitro experiments, tumor weight was not decreased by canagliflozin. In addition, the serum insulin level, but not body weight or blood glucose level, was decreased by canagliflozin. The number of cells positive for Ki67 was slightly decreased by canagliflozin, but this was not statistically significant. In conclusion, SGLT2 is expressed in human lung cancer tissue and cell lines, and the SGLT2 inhibitor, canagliflozin, attenuated proliferation of A549 lung cancer cells by inhibiting cell cycle progression in vitro but not in vivo.

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Acknowledgments

We thank Mitchell Arico from Edanz (https://en-author-services.edanz.com/ac) for editing the English text of a draft of this manuscript.

Funding

T.N. received lecture fees from MDS, Sumitomo Dainippon Pharma and Ono Pharmaceutical, and research grants from Sumitomo Dainippon Pharma and Mitsubishi Tanabe Pharma. T.Y. received research grants from MSD, Eli Lilly Japan, Takeda Pharmaceutical and Nippon Boehringer Ingelheim. D.K. received lecture fees from Eli Lilly Japan, Novo Nordisc Pharma and Takeda Pharmaceutical and Novartis Pharma, and research grants from Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Sumitomo Dainippon Pharma and Ono Pharmaceutical.

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Authors and Affiliations

  1. Department of General Thoracic, Breast and Pediatric Surgery, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Leona Yamamoto, Shinichi Yamashita & Akinori Iwasaki

  2. 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

  3. 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

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

    Takako Kawanami, Yuriko Hamaguchi, Toru Shigeoka, Tsuyoshi Horikawa, Yuki Tanaka & Daiji Kawanami

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

    Toshihiko Yanase

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  1. Leona Yamamoto
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  2. Shinichi Yamashita
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  3. Takashi Nomiyama
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  4. Takako Kawanami
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  9. Toshihiko Yanase
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Contributions

L. Y., T. K. and Y. H. performed experiments and data analysis. T. N. and S. Y. wrote the manuscript and conceived the research hypothesis and design. T. S., T. H., Y. F-T., T. Y., D. K., and A. I. reviewed the manuscript.

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Correspondence to Shinichi Yamashita or Takashi Nomiyama.

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Yamamoto, L., Yamashita, S., Nomiyama, T. et al. Sodium-glucose cotransporter 2 inhibitor canagliflozin attenuates lung cancer cell proliferation in vitro. Diabetol Int 12, 389–398 (2021). https://doi.org/10.1007/s13340-021-00494-6

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  • DOI: https://doi.org/10.1007/s13340-021-00494-6

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