Enhancement of Doxorubicin Cytotoxicity by Verapamil in Human Breast Cancer Cells

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 Al-harthy et al.; JPRI, 27(6): 1-10, 2019; Article no.JPRI.49253 2 DOX plus VER. Moreover, combined treatment with VER and DOX significantly increased percentage of early apoptosis and cells arrested in G 0 /G 1 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. Original Research Article

Antitumor activities of carboplatin–doxorubicin–ZnO complexes in different human cancer cell lines (breast, cervix uteri, colon, liver and oral) under UV exposition

“…RGDfC-Se Derlin1-siRNA ¼ 200 nM Xia et al [7] Human liver cancer cells (HepG2) Galactose-Se Doxorubicin ¼ 4 lg/mL Xia et al [8] Cervical cancer cells (HeLa) Hyaluronic acid-Se Doxorubicin ¼ 4 lg/mL Vu et al [9] Human myeloid leukaemia -Doxorubicin ¼ 0.5-1 lg/mL Malky et al [10] Human breast adenocarcinoma (MCF-7) -Doxorubicin ¼ 0.25-1 lg/mL Christowitz et al [11] Murine breast tumour (E0771) -Doxorubicin ¼ 6-15 mg/mL Al-Harthy et al [12] Human breast adenocarcinoma (MCF-7) -Doxorubicin ¼ 13-36 lg/mL Matcovschii et al [13] Human glioblastoma -Doxorubicin ¼ 2-20 lg/mL Allen et al [14] Mouse gonads -Carboplatin ¼ 0.1-1 lg/mL Cisplatin ¼ 0.5-5 lg/mL Kuittinen et al [15] Ovarian cancer cells -Carboplatin ¼ 0.1-50 lg/mL Paclitaxel ¼ 1-10 ng/mL Corn et al [16] Human prostate cancer -Carboplatin ¼ 3-4 mg/mL Cabazitaxel ¼ 20-25 mg/mL Lopes et al [17] Human and mouse ovary -Doxorubicin ¼ 1-2 lg/mL Cisplatin ¼ 5-10 lg/mL Yu et al [18] Bladder cancer (MBT-2) -Doxorubicin ¼ 0.62 lg/mL Lipodoxorubicin ¼ 130 lg/mL Eroglu et al [19] Human breast adenocarcinoma (MCF-7) -Doxorubicin ¼ 0.01 mg/mL 5-Fluorouracil ¼ 6 mg/mL Propranolol ¼ 30 mg/mL Escobar-Resendiz et al [20] Human lung carcinoma cell (A549)…”

“…Furthermore, the dosage of chemo drugs required to reach the targeted tumour site, which is associated with variations in individual patients, tumour microenvironments and complications in the molecular biology of cancer, is still under debate (Table 1). Sometimes, administering single chemo drugs for a long period of time is a challenging task because of the development of chemoresistance and severe side effects [1][2][3][4][5][6][7][8][9][10][11][12][13]. A double-chemo drug regimen is sufficient for very small tumours [14][15][16][17][18], whereas other chemo drugs might be used if these methodologies are not effective [19,20].…”