Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production

Bushra Mdkhana; Dana M Zaher; Shifaa M Abdin; Hany A Omar

doi:10.1016/j.phymed.2021.153470

Tangeretin boosts the anticancer activity of metformin in breast cancer cells via curbing the energy production

Phytomedicine. 2021 Mar:83:153470. doi: 10.1016/j.phymed.2021.153470. Epub 2021 Jan 17.

Authors

Bushra Mdkhana¹, Dana M Zaher¹, Shifaa M Abdin¹, Hany A Omar²

Affiliations

¹ Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
² Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511 Egypt. Electronic address: hanyomar@sharjah.ac.ae.

PMID: 33524703
DOI: 10.1016/j.phymed.2021.153470

Abstract

Background: Breast cancer is the first leading cause of women cancer-related deaths worldwide. While there are many proposed treatments for breast cancer, low efficacy, toxicity, and resistance are still major therapeutic obstacles. Thus, there is a need for safer and more effective therapeutic approaches. Because of the direct link between obesity and carcinogenesis, energy restriction mimetic agents (ERMAs) such as the antidiabetic agent, metformin was proposed as a novel antiproliferative agent. However, the anticancer dose of metformin alone is relatively high and impractical to be implemented safely in patients. The current work aimed to sensitize resistant breast cancer cells to metformin's antiproliferative effect using the natural potential anticancer agent, tangeretin.

Methods: The possible synergistic combination between metformin and tangeretin was initially evaluated using MTT cell viability assay in different breast cancer cell lines (MCF-7, MDA-MB-231, and their resistant phenotype). The possible mechanisms of synergy were investigated via Western blotting analysis, reactive oxygen species (ROS) measurement, annexin/PI assay, cell cycle analysis, and wound healing assay.

Results: The results indicated the ability of tangeretin to improve the anticancer activity of metformin. Interestingly, the improved activity was almost equally observed in both parental and resistant cancer cells, which underlines the importance of this combination in cases of the emergence of resistance. The synergy was mediated through the enhanced activation of AMPK and ROS generation in addition to the improved inhibition of cell migration, induction of cell cycle arrest, and apoptosis in cancer cells.

Conclusion: The current work underscores the importance of metformin as an ERMA in tackling breast cancer and as a novel approach to boost its anticancer activity via a synergistic combination with tangeretin.

Keywords: AMPK; Breast cancer resistance; energy restriction; metformin; tangeretin.

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Drug Resistance, Neoplasm / drug effects
Female
Flavones / administration & dosage
Humans
MCF-7 Cells
Metformin / administration & dosage

Substances

Flavones
Metformin
tangeretin