Abstract
PurposeP-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound.MethodsThe in vitro and in vivo activity was determined using the MTT assay and human breast cancer xenograft models. The gene and protein expression of P-glycoprotein were determined using real-time polymerase chain reaction and the Western blotting technique, respectively. ABCB-1 bioactivity was tested by fluorescence microscopy, multi-mode microplate reader, and flow cytometry. The intracellular levels of ATP, HK-II, and ATPase activity were based on an assay kit according to the manufacturer’s instructions.Results3-Bromopyruvate treatment led to marked decreases in the IC50 values of selected chemotherapeutic drugs [e.g., doxorubicin (283 folds), paclitaxel (85 folds), daunorubicin (201 folds), and epirubicin (171 folds)] in MCF-7/ADR cells. 3-Bromopyruvate was found also to potentiate significantly the antitumor activity of epirubicin against MCF-7/ADR xenografts. The intracellular level of ATP decreased 44%, 46% in the presence of 12.5.25 µM 3-Bromopyruvate, whereas the accumulation of rhodamine 123 and epirubicin (two typical P-glycoprotein substrates) in cells was significantly increased. Furthermore, we found that the mRNA and the total protein level of P-glycoprotein were slightly altered by 3-Bromopyruvate. Moreover, the ATPase activity was significantly inhibited when 3-Bromopyruvate was applied.ConclusionWe demonstrated that 3-Bromopyruvate can reverse P-glycoprotein-mediated efflux in MCF-7/ADR cells. Multidrug resistance reversal by 3-Bromopyruvate occurred through at least three approaches, namely, a decrease in the intracellular level of ATP and HK-II bioactivity, the inhibition of ATPase activity, and the slight decrease in P-glycoprotein expression in MCF-7/ADR cells.
Highlights
Breast cancer is one of the most critical threats to women, and its incidence is increasing year by year [1]
While advancements in breast cancer treatment and prevention have emerged over the last decade, multidrug resistance (MDR) has been a main cause of breast cancer chemotherapy failure [2]
It is reasonable to deduce that 3-BrPA can efficiently reverse the MDR of ABCB-1/P-gp overexpressing tumor cells, which with a high demand for ATP produced by glycolysis
Summary
Breast cancer is one of the most critical threats to women, and its incidence is increasing year by year [1]. Chemotherapy and endocrine therapy are still predominantly used for the treatment of breast cancer. While advancements in breast cancer treatment and prevention have emerged over the last decade, multidrug resistance (MDR) has been a main cause of breast cancer chemotherapy failure [2]. The mechanisms underlying MDR are rather complex, and among them, transporter-mediated efflux is a major one that has received enormous attention [3,4]. The efflux transporters, including P-glycoprotein (ABCB-1/P-gp)[5], multidrug resistance proteins (MRPs) [6], and breast cancer resistance protein (BCRP) [7] are over-expressed in many cancer cells, limiting the entry of the drug into the inside of cells and conferring the resistance of cells to the drugs [4]. It is still difficult to predict P-gp activity toward a new compound, many structure-activity relationships have been established
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