Shenmai injection suppresses multidrug resistance in MCF-7/ADR cells through the MAPK/NF-κB signalling pathway

Pharm Biol. 2020 Dec;58(1):276-285. doi: 10.1080/13880209.2020.1742167.

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.

Keywords: P-glycoprotein; apoptosis; rhodamine 123.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Down-Regulation / drug effects
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology*
  • Doxorubicin / therapeutic use
  • Drug Combinations
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Drugs, Chinese Herbal / administration & dosage
  • Drugs, Chinese Herbal / pharmacology*
  • Drugs, Chinese Herbal / therapeutic use
  • Female
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / metabolism*
  • Rhodamine 123 / metabolism
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Drug Combinations
  • Drugs, Chinese Herbal
  • NF-kappa B
  • fructus schizandrae, radix ginseng, radix ophiopogonis drug combination
  • Rhodamine 123
  • Doxorubicin

Grants and funding

This work was supported by grants from Zhejiang Provincial Bureau of Traditional Chinese Medicine [2019ZB019, 2019ZB020, 2018ZB027] the Natural Sciences Foundation of Zhejiang [LY17H310009, LQY18H160001, LQY19H280002] and the Sciences and Technology Department of Zhejiang Province [2016F30009].