Abstract
Context Shenmai Injection (SMI) is usually used to treat atherosclerotic coronary heart disease and viral myocarditis in China. However, the effect of SMI on multidrug resistance has not been reported. Objective To investigate the reversal effect of SMI in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) and explore the related molecular mechanisms. Materials and methods The effect of SMI (0.25, 0.5, 1 mg/mL) to reverse chemoresistance in MCF-7/ADR cells was elucidated by MTT, HPLC-FLD, DAPI staining, flow cytometric analysis, western blotting. At the same time, in vivo test was conducted to probe into the effect of SMI on reversing ADR resistance, and verapamil (10 μM) was used as a positive control. Results The results showed that the toxicity of ADR to MCF-7/ADR cells was strengthened significantly after treated with SMI (0.25, 0.5, 1 mg/mL), the IC50 of ADR was decreased 54.4-fold. The intracellular concentrations of ADR were increased 2.2-fold (p < 0.05) and ADR accumulation was enhanced in the nuclei (p < 0.05). SMI could strongly enhance the ADR-induced apoptosis and increase intracellular rhodamine 123 accumulation in MCF-7/ADR cells. Additionally, a combination of ADR and SMI (5 mg/kg) could dramatically reduce the weight and volume of tumour (p < 0.05). Furthermore, the results revealed that SMI might reverse MDR via inhibiting ADR-induced activation of the mitogen-activated protein kinase/nuclear factor (NF)-κB pathway to down-regulated the expression of P-glycoprotein (P-gp). Discussion and conclusions SMI could potentially be used to treat ADR-resistance. This suggests possibilities for future clinical research.
Highlights
Considered as a vital treatment for cancer, chemotherapy drugs are usually effective in the early stage
We systemically evaluated whether Shenmai Injection (SMI) could reverse the multidrug resistance (MDR) of the breast cancer MCF-7/ADR cell line and investigated the mechanism by which it produces reversal effects
The results of MTT assay indicated that the ADR IC50 values of MCF-7 cells and MCF-7/ADR cells were 20.46 and 286.28 lM, which suggests that MCF-7/ADR cells were more resistant to ADR than MCF-7 cells for approximately 14-fold (Figure 2(A))
Summary
Considered as a vital treatment for cancer, chemotherapy drugs are usually effective in the early stage. In the middle and late stages, the efficacy of chemotherapy drugs is significantly reduced, and some types of cancer are resistant to multidrug chemotherapy. This phenomenon is called multidrug resistance (MDR). MDR is regarded as a major barrier to the efficacy of chemotherapy treatment (Rivera 2010). Many studies have suggested that the overexpression of P-glycoprotein (P-gp), a binding target of antitumour drugs which is located on the cell membrane, is the most frequent cause of MDR (Gottesman and Pastan 1993). Identifying effective MDR reversal agents to maintain the efficacy of chemotherapeutic agents is urgently needed
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