Reversal of P-glycoprotein-mediated multidrug resistance by guggulsterone in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.

Multidrug resistance (MDR) has been a major problem in cancer chemotherapy. The development of P-glycoprotein inhibitors could be effective to reverse multidrug resistance. The aim of this study was to observe the effects of guggulsterone, the active component of gugulipid, on multidrug resistance in doxorubicin-resistant K562 cells (K562/DOX) and the parental K562 cells. Its cytotoxicity and reversal effects on multidrug resistance were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double staining. The effects of guggulsterone on P-glycoprotein activity were evaluated by measuring rhodamine 123 (Rh123)-associated mean fluorescence intensity and P-glycoprotein expression on the basis of the flow cytometric technology, respectively. The results showed that guggulsterone up to 100 microM had little cytotoxicity against K562/DOX cells. When combined with doxorubicin, it significantly promoted the sensitivity of K562/DOX cells toward doxorubicin through increasing intracellular accumulation of doxorubicin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of guggulsterone on P-glycoprotein activity was the major cause of increased stagnation of doxorubicin inside K562/DOX cells, indicating that guggulsterone may effectively reverse multidrug resistance in K562/DOX cells via inhibiting expression and drug-transport function of P-glycoprotein.