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17.09.2020 | Preclinical study

Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer

verfasst von: Lei Xue, Fengju Chen, Fei Yue, Laura Camacho, Sushma Kothapalli, Guanyun Wei, Shixia Huang, Qianxing Mo, Fei Ma, Yi Li, Sao Jiralerspong

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2021

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Abstract

Purpose

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC.

Methods

We treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings.

Results

The combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27^Kip1 and decreased the level of the p27^Kip1 E3 ligase SCF^Skp2.

Conclusions

We conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCF^Skp2 and subsequent stabilization of the cell cycle inhibitor p27^Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.

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Titel: Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer
verfasst von: Lei Xue
Fengju Chen
Fei Yue
Laura Camacho
Sushma Kothapalli
Guanyun Wei
Shixia Huang
Qianxing Mo
Fei Ma
Yi Li
Sao Jiralerspong
Publikationsdatum: 17.09.2020
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2021
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05927-5

Springer Medizin

Metformin and an insulin/IGF-1 receptor inhibitor are synergistic in blocking growth of triple-negative breast cancer