Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. The progression, metastasis and drug resistance of breast cancer cells were suggested to be driven by a special population within the tumor called cancer stem cells (CSC). Targeting CSC is extremely challenging due to the high expression levels of ATP-binding cassette (ABC) transporters which facilitates the multi drug resistance (MDR) capacity of CSC. The aim of this work was to test whether Energy restriction mimetic agents (ERMAs) as OSU-CG5 can counteract cancer multidrug resistance by limiting the availability of energy in CSC. In addition to exploit the mechanistic synergy between OSU-CG5 and a conventional chemotherapeutic agent as Doxorubicin.
Doxorubicin-resistant breast cancer cells (MCF-7 and MDA-231 cell lines) were generated by the exposure to increasing concentrations of doxorubicin. The degree of resistance was assessed by MTT cell viability assay and immunofluorescence. In addition, the alteration in the expression of ABC transporter proteins was determined by Western blot. The induction of CSC was assessed by flow cytometry looking at the expression of breast CSC markers CD44 and CD24. The antitumor effect of OSU-CG5 and/or doxorubicin, in addition to the mechanistic synergy between them was determined by MTT assay, caspase3/7 assay and Western blotting.
The generated doxorubicin-resistant breast cancer cells (MCF-7 and MDA-231 cell lines) showed less sensitivity to doxorubicin and an increase in breast cancer CD44+/CD24low cells, in addition to increased expression of ABC proteins. This stem cell enriched population was declined and the anticancer effect of doxorubicin was significantly synergized by its combination with OSU-CG5, suggesting that ERMAs preferentially inhibit stem/progenitors in breast cancer cells.
The results suggested that targeting breast CSC population by ERMAs could be a rational strategy to minimize their multi-drug resistance, and the combination with classical chemotherapeutic agent as doxorubicin may represent a clinically relevant strategy for cancer treatment that ultimately lead to new approaches to improve the survival of cancer patients.
University of Sharjah
Al Jalila Foundation, United Arab Emirates (Grant number AJF201610)
All authors have declared no conflicts of interest.