Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer
| Autor: | Gary Groot, Gerald F. Davies, John R. Gordon, Liubov Lobanova, Wojciech Dawicki, Matthew Bowen, Troy A. A. Harkness, Terra Arnason |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Cancer Treatment lcsh:Medicine Drug resistance Biochemistry Histones Mice 0302 clinical medicine Breast Tumors Medicine and Health Sciences Medicine Enzyme assays Colorimetric assays lcsh:Science Bioassays and physiological analysis Energy-Producing Organelles Multidisciplinary MTT assay Pharmaceutics Histone deacetylase inhibitor Drug Synergism Metformin Mitochondria Oncology 030220 oncology & carcinogenesis Female Cellular Structures and Organelles Cancer Prevention medicine.drug Research Article Drug Research and Development medicine.drug_class Breast Neoplasms Bioenergetics 03 medical and health sciences Breast cancer Drug Therapy In vivo Cell Line Tumor Breast Cancer DNA-binding proteins Animals Humans Cell Proliferation Pharmacology Chemotherapy Cancer prevention business.industry lcsh:R Estrogen Receptor alpha Cancer Cancers and Neoplasms Biology and Life Sciences Proteins Cell Biology medicine.disease Xenograft Model Antitumor Assays Research and analysis methods 030104 developmental biology Doxorubicin Drug Resistance Neoplasm Biochemical analysis Cancer research lcsh:Q business |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 12, p e0187191 (2017) |
| ISSN: | 1932-6203 |
| Popis: | Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin. Metformin is prescribed globally to improve insulin sensitivity, including in those individuals with Type 2 Diabetes Mellitus (DM2). We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment, and provide evidence that metformin may function through a mechanism involving post-translational histone modifications via an indirect histone deacetylase inhibitor (HDACi) activity. We find that metformin, at low physiological concentrations, reduces the expression of multiple classic protein markers of MDR in vitro and in preliminary in vivo models. Our demonstration that metformin can prevent MDR development and resensitize MDR cells to chemotherapy in vitro, provides important medical relevance towards metformin's potential clinical use against MDR cancers. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|