Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways

  • Authors:
    • Yun‑Suk Kwon
    • So‑Young Chun
    • Hong‑Yan Nan
    • Kyung‑Soo Nam
    • Chuhee Lee
    • Soyoung Kim
  • View Affiliations

  • Published online on: December 12, 2018     https://doi.org/10.3892/ol.2018.9827
  • Pages: 2523-2530
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Abstract

Recent studies have reported that metformin (Met), the first‑line medication for the treatment of type 2 diabetes, exhibited anticancer and chemoprotective effects in diverse cancer cells. In this study, we investigated the effects of Met on the drug‑resistance of 4T1 murine breast cancer tumorspheres (TS) and the mechanism responsible for its drug‑resistance. 4T1 TS exhibited accumulations of cells at the G0/G1 phase compared with cells in monolayer culture, which suggested the majority of cells in TS were quiescent. Furthermore, it was identified that activations of the signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT) signaling pathways in 4T1 TS conferred drug‑resistance to doxorubicin (Dox) and lapatinib (Lapa). However, Met selectively targeted TS rather than cells in monolayer culture and increased the cytotoxic effect of Dox on TS by inhibiting activations of the STAT3 and AKT signaling pathways. These observations suggested that inhibitions of STAT3 and AKT underlie the selective cytotoxic effects of Met on TS. In addition, Met exhibited synergistic antitumor effects with Dox on 4T1 tumor‑bearing BALB/c mice. Our findings suggest that combinations of Met and cytotoxic anticancer drugs may offer an advantage for treating drug‑resistant breast cancer.
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February-2019
Volume 17 Issue 2

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Spandidos Publications style
Kwon YS, Chun SY, Nan HY, Nam KS, Lee C and Kim S: Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways. Oncol Lett 17: 2523-2530, 2019
APA
Kwon, Y., Chun, S., Nan, H., Nam, K., Lee, C., & Kim, S. (2019). Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways. Oncology Letters, 17, 2523-2530. https://doi.org/10.3892/ol.2018.9827
MLA
Kwon, Y., Chun, S., Nan, H., Nam, K., Lee, C., Kim, S."Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways". Oncology Letters 17.2 (2019): 2523-2530.
Chicago
Kwon, Y., Chun, S., Nan, H., Nam, K., Lee, C., Kim, S."Metformin selectively targets 4T1 tumorspheres and enhances the antitumor effects of doxorubicin by downregulating the AKT and STAT3 signaling pathways". Oncology Letters 17, no. 2 (2019): 2523-2530. https://doi.org/10.3892/ol.2018.9827