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Constraining Multi‐Drug Resistance in Breast Cancer Cells by Energy Restriction
Author(s) -
Omar Hany A.,
Zaher Dana M.,
Tolba Mai F.,
AlTel Taleb H.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.675.18
Subject(s) - abcg2 , doxorubicin , cancer research , multiple drug resistance , population , cancer cell , abcc1 , cd44 , pharmacology , context (archaeology) , apoptosis , breast cancer , cancer , downregulation and upregulation , biology , cancer stem cell , drug resistance , cell , medicine , atp binding cassette transporter , chemotherapy , biochemistry , genetics , paleontology , environmental health , transporter , gene
The resistance of breast cancer to chemotherapy constitutes a major roadblock for a successful treatment. The development of multidrug resistance (MDR) is one of the common mechanisms for resistance to various chemotherapeutic agents including doxorubicin (DOX). In this context, we tested the hypothesis that energy restriction mimetic agents (ERMAs) such as OSU‐GC5 could synergize the antitumor effects of DOX through restraining the availability of energy that is essential for the activity of MDR efflux carriers. Subclones of MCF‐7 and MDA‐MB231 breast cancer cell lines resistant to DOX have been established by subjecting the cells to increasing concentrations of DOX over 6 months. The MDR phenotype was verified via the upregulated expression of ATP binding cassette (ABC) protein ABCC1, ABCB1 and ABCG2 together with a reduced cellular accumulation of DOX. Fluorescence‐activated cell sorting analysis indicated that the percentage of CD44 + /CD24 − stem cell‐like population was enriched in the resistant subclones. Combination analysis demonstrated a synergistic antitumor interaction between OSU‐CG5 and DOX accompanied by augmented activation of mitochondrial apoptosis and AMPK signaling as verified by Western blot analysis. Co‐treatment with OSU‐CG5 and DOX significantly reduced cellular ATP content and NADP + /NADPH ratio, while it significantly enhanced ROS production. Concomitant exposure to ROS scavenger, N‐acetylcysteine, eliminated the synergy between OSU‐CG5 and DOX. This study recommended OSU‐CG5 as a promising adjuvant to overcome MDR resistance. This combinatorial strategy can be extrapolated to breast cancer treatment regardless of the hormone receptor expression status, which encourages future research in syngeneic murine tumor xenograft models. Support or Funding Information This work was supported by a research grant from Al Jalila Foundation, United Arab Emirates (Grant number AJF201610) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .