Reversal of multidrug resistance in breast cancer cells by a combination of ursolic acid with doxorubicin

Multidrug resistance (MDR) has seriously affected or hindered the effect of chemotherapy. Ursolic acid (UA) as a natural compound exhibits a number of potential biological effects including antitumor. Searching for the reversal agents from the natural products has been an effective strategy recently applied in overcoming the MDR. So in this study, the reversal effect of UA on the MDR and involved mechanisms were investigated via a multidrug-resistant MCF-7/ADR cells model and ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analytical methods. The synergistic effects were yielded by the combination of UA and Dox based on the investigation of the intracellular accumulation, the P-glycoprotein (P-gp) mediated transport, the energy metabolism including glycolysis, tricarboxylic acid (TCA) cycle, and glutamine metabolism as well as related amino acid metabolism. Obtained results showed that the UA could increase amount of doxorubicin (Dox) entering the cell to accumulate in nuclei, decrease the efflux ratio of digoxin comparable to the effects of the known inhibitor verapamil by acting as a P-gp substrate, decrease the content of intracellular alanine, lactate, pyruvate, glucose, alpha-ketoglutarate, glutamate, glutamine, aspartate, serine, and glycine. Taken together, inhibition of P-gp function and disruption of the metabolism of energy and related amino acids could be the key mechanisms by which UA could reverse the MDR. The findings also indicated that UA could be a potential alternative adjuvant antitumour herbal medicine to resensitize cells with MDR to chemotherapeutic agents. (C) 2018 Elsevier B.V. All rights reserved.