Enhancement of Doxorubicin Cytotoxicity by Verapamil in Human Breast Cancer Cells
Sameer E. Al-harthy
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Mashael S. Al-Motairi
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Huda M. Al-Kreathy
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Fatemah O. Kamel
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Mohamed M. Sayed-Ahmed
Pharmacology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt.
Etimad Abbas Huwait
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Hamdan S. Al-Malkey
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Abdel-Moneim M. Osman *
Pharmacology Unit, National Cancer Institute, Cairo University, Cairo 11796, Egypt
*Author to whom correspondence should be addressed.
Abstract
Background: Worldwide, breast cancer is a main cause of morbidity and mortality in females. Doxorubicin (DOX) is an anthracycline anticancer drug and most commonly employed in polychemotherapy protocols in the treatment of solid and hematological tumors. Unfortunately, its optimal clinical benefit is limited secondary to the rapid development of DOX resistance and therapeutic failure.
Aim: Therefore, the current study has been initiated to investigate the possible mechanisms whereby the calcium channel blocker Verapamil (VER) could decrease DOX resistance and enhance the cytotoxic activity of DOX against the growth of human breast cancer cells.
Methodology: To achieve the ultimate goal of this study, we have examined DOX-induced cytotoxicity, apoptosis, alteration in the function of multidrug resistance proteins and cell cycle phase distribution against MCF-7 cell line in presence and absence of Verapamil.
Results: Addition of VER enhanced the cytotoxic effect of DOX against the growth of MCF-7 cells which manifested as a significant decrease in the IC50 from 36 µg/ml for DOX alone to 13 µg/ml for DOX plus VER. Moreover, combined treatment with VER and DOX significantly increased percentage of early apoptosis and cells arrested in G0/G1 phase when compared to DOX alone. In addition, VER significantly increased DOX cellular uptake through inhibition of the function of multidrug resistant proteins.
Conclusion: VER treatment enhanced the cytotoxic activity of DOX against the growth of MCF-7 cells secondary to increase its cellular accumulation. The observed increase in DOX uptake by VER was parallel to increased accumulation of Rho-123 dye which my point to the contribution of inhibition of multidrug resistant proteins by VER in the enhancement of DOX cytotoxicity.
Keywords: Doxorubicin, verapamil, cytotoxicity, potentiation, breast cancer cells.