Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line

Kitazono,Satoru; Takiguchi,Yuichi; Ashinuma,Hironori; Saito-Kitazono,Miyako; Kitamura,Atsushi; Chiba,Tetsuhiro; Sakaida,Emiko; Sekine,Ikuo; Tada,Yuji; Kurosu,Katsushi; Sakao,Seiichiro; Tanabe,Nobuhiro; Iwama,Atsushi; Yokosuka,Osamu; Tatsumi,Koichiro

doi:10.3892/ijo.2013.2120

Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line

Authors:
- Satoru Kitazono
- Yuichi Takiguchi
- Hironori Ashinuma
- Miyako Saito-Kitazono
- Atsushi Kitamura
- Tetsuhiro Chiba
- Emiko Sakaida
- Ikuo Sekine
- Yuji Tada
- Katsushi Kurosu
- Seiichiro Sakao
- Nobuhiro Tanabe
- Atsushi Iwama
- Osamu Yokosuka
- Koichiro Tatsumi
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Affiliations: Department of Respirology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan, Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan, Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan, Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan
Published online on: October 3, 2013 https://doi.org/10.3892/ijo.2013.2120
Pages: 1846-1854
Copyright: © Kitazono et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Cancer chemotherapy, including molecular targeted therapy, has major limitations because it does not kill all the cancer cells; the residual cells survive until they acquire chemoresistance. In the present study, the combined effects of metformin and gefitinib were examined in vivo in a mouse xenograft model, inoculated with a human lung adenocarcinoma cell line that possesses an activating epidermal growth factor receptor mutation. The mechanism of the interaction was further elucidated in vitro. Metformin did not suppress the growth of already established tumors, nor did metformin augment tumor shrinkage by gefitinib. However, metformin significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting the specific effect of metformin on the residual cells. Cytotoxicity of metformin was characterized by the absence of apoptosis induction and unremarkable cell cycle shift in vitro. The residual cell population after treatment with gefitinib was characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy may represent an effective novel strategy for the treatment of cancer. Elucidating the mechanism of metformin cytotoxicity provides insights into future development of anticancer therapeutics.

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