Abstract
The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX) on P-gp-mediated multidrug resistance (MDR) in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 μmol/L PTX in the presence or absence of 1.2 μmol/L vincristine (VCR). Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs), especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells.
Highlights
A major problem in cancer chemotherapy is the development of a multidrug resistance (MDR)phenotype in cancer cells
The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene and an ABCB1 member of the ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutic agents, resulting in the development of MDR in cancer cells and causing them to become insensitive to a range of different cytostatic drugs [1,2]
Additional reports suggest that PTX administration might increase the effectiveness of antitumor chemotherapy [7,8], and our previous studies demonstrated that PTX induced the reversal of vincristine (VCR) and/or adriamycin resistance in P-gp-positive L1210/VCR (P-gp positive cell variant of L1210 cells were obtained by selection with VCR) mouse leukemia cells [9,10]
Summary
A major problem in cancer chemotherapy is the development of a multidrug resistance (MDR)phenotype in cancer cells. A major problem in cancer chemotherapy is the development of a multidrug resistance (MDR). Additional reports suggest that PTX administration might increase the effectiveness of antitumor chemotherapy [7,8], and our previous studies demonstrated that PTX induced the reversal of vincristine (VCR) and/or adriamycin resistance in P-gp-positive L1210/VCR (P-gp positive cell variant of L1210 cells were obtained by selection with VCR) mouse leukemia cells [9,10]. The mechanism of PTX action on drug resistance of cancer cells still remains unclear. P-gp-positive L1210/VCR mouse leukemia cells were found to be defective in drug-induced apoptosis, even for drugs that are not substrates of P-gp [11]. Sensitization of cervical cancer cells to adriamycin by PTX was found to be associated with more pronounced apoptosis [12]. We tested the hypothesis that PTX restores the sensitivity of L1210/VCR cells to VCR due to a decrease in
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