Reversal of P-glycoprotein-dependent resistance to adriamycin by 5-bromotetrandrine in K562/A02 cell line

13557 Background: Bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), could effectively reverse P-glycoprotein mediated multidrug resistance. The present study aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), in vitro. Methods: The inhibitory effects of adriamycin (ADM) used alone or in combination with BrTet or Tet on the proliferation of K562 and K562/A02 cells were evaluated by MTT assay. ADM accumulation and the protein levels of P- glycoprotein (P-gp) were analyzed by fluorospectrophotometry, respectively. The mRNA levels of P-gp were determined by RT-PCR. The in vivo effect of Tet was investigated using nude mice grafted with sensitive human leukemia cell line K562 and MDR cell line K562/A02. Results: BrTet at 0.25, 0.5 and 1μM reversed ADM resistance in MDR K562/A02 cells dose-dependently and its potency was greater than that of Tet at the same concentrations. Fluorospectrophotometric assay showed that BrTet significantly increased the intracellular accumulation of ADM in K562/A02 cells in a dose-dependent manner. BrTet also inhibited the overexpression of P-gp in K562/A02 cells, and had an effect of decrease on mdr1 expression. In nude mice bearing K562 xenografts on the left flank and K562/A02 xenografts on the right flank, i.p. injection of 10 mg/kg BrTet significantly enhanced the antitumor activity of ADM against K562/A02 xenografts with inhibitory rates of 26.1%, while ADM alone inhibited the growth of KBv200 xenografts by only 5.8%. No enhancement by BrTet was seen in K562 xenografts. Conclusions: BrTet showed significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase in intracellular accumulation of anticancer drugs. BrTet may be a promising MDR modulator for eventual assessment in the clinic. No significant financial relationships to disclose.