ALGERIAN PROPOLIS: BETWEEN PROTECTION OF NORMAL CELLS AND POTENTIALISATION OF THE ANTICANCER EFFECTS OF DOXORUBICIN AGAINST BREAST CANCER CELLS VIA P-GLYCOPROTEIN INHIBITION AND CELL CYCLE ARREST IN THE S PHASE

Breast cancer is a common cancer and is the leading cause of cancer-related deaths among women worldwide. Studies have shown that breast cancer is a heterogeneous tumor with varying response to treatments. The clinical use of doxorubicin (Dox) in the treatment of cancer is limited by its cardiotoxicity which results in often fatal heart failure and the development of multidrug resistance. Therefore, new therapeutic strategies and targets are underscored. Propolis has been reported to show a broad spectrum of biological activities including anticancer activity. In this study, we investigated the role of propolis on the antitumor effects of Dox on breast cancer cells (MDA-MB-231) and its ability to provide protection against Dox-mediated damage on normal cells (MRC-5). Modifications in cell viability, apoptosis induction, cell cycle progression and permeability glycoprotein (P-gp) activity of breast cancer cells in vitro were evaluated. Propolis combined with Dox inhibited cell growth in a dose dependent manner by inducing cell cycle arrest in the S phase and caspase-dependent apoptosis. In the presence of propolis, the IC50 of Dox against MDA-MB-231 cells decreased by 10-fold. The increased sensitivity of cancer cells to the combined treatment was explained by the capacity of propolis to cause a significant increase in Dox content in MDA-MB-231. Very interestingly, Algerian propolis showed its ability to inhibit efficiently P-gp function in comparison with verapamil, reference P-gp modulator, which proves the efficacy of propolis to reverse the problem of multidrug resistance. Our results showed also that propolis could protect normal cells from deleterious effects of Dox by amelioration of cell viability. In conclusion, the obtained results indicate that Algerian propolis potentiated the antitumor effects of Dox on breast cancer cells and could reduce the problem of multidrug resistance. Therefore, Algerian propolis may be an effective agent in a combined treatment with Dox for increased therapeutic efficacy against breast cancer. Clinically, our results are relevant because with this combined therapy it may be possible to counter the problem of cancer cell resistance while reducing the problem of toxicity on normal cells.