| Circumvention of multidrug resistance is a new field of investigation in cancer chemotherapy, and potent and safe multidrug resistance inhibitors are needed for clinical use. Pyronaridine (PND), a novel antimalarial drug, was evaluated as resistance reversal agent in cells and xenografts models exhibiting multidrug resistance (MDR) phenotype. Our results showed that: (1) In vitro, PND synergistically potentate the cytotoxicity of doxorubicin to the Pgp-overexpressing K562/A02 and MCF-7/ADM, and partly reverse MRP-overexpressing HL-60/ADM cells at concentrations of 1-4 microM, but hardly had any synergistic effect at the same concentration in the parental cell lines. PND was more potent than verapamil, a known modulator of multidrug-resistance. (2) PND increased the intracellular accumulation of doxorubicin and inhibited the P-glycoprotein pump-efflux activity in a time-related manner. Moreover, it did not reduce the expression of the mdr1 gene in K562/A02 cell as evaluated by RT-PCR assay. (3) The structure-activity relationship analysts of antimalarial drugs indicated that these compounds share broad structural similarities: the quinoline ring derived from a common plane, lipophilic(logP≥2.50), and a active nitrogen atom in the hydrophobic moiety, which maybe influence the MDR-reversing activities. (4) PND significantly enhanced the in vivo antitumor activity of doxorubicin in human leukemia xenografts model, with no apparent alteration of pharmacokinitic. The toxicity of combined treatment, indicated by body weight loss, was moderate and reversible. (5) In vivo study, PND was able to block cell cycle progression, induce apoptotic cell death and inhibit angiogenesis that may occur indirectly by doxorubicin targeting the damage. Thus, these results indicate that PND is a promising new candidate for revering multidrug resistance and will be applied to clinical trails.
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