Oleanolic acid derivative methyl 3,11-dioxoolean-12-en-28-olate targets multidrug resistance related to ABCB1

Multidrug resistance (mdr) in leukemia patients is a great incentive to the development of new drugs. in a search for potential multidrug resistance modulators we tested a group of oleanolic acid (oa) analogues modified at c-3,c-11,c-12 and c-28 using an experimental model consisting of three human acute lymphoblastic leukemia cell lines (ccrf-cem and the multidrug resistant sublines ccrf-vcr1000 and ccrf-adr5000). the most effective compound,methyl 3,11-dioxoolean-12-en-28-olate (dioxol) was more potent in cell viability inhibition than its precursor - oa,and showed similar or even higher activity in the drug resistant than in the wild-type cells. resistance factor (rf) values obtained for ccrf-vcr1000 and ccrf-adr-5000 cells using mtt assay were 0.7 and 0.8 (24 h of treatment) and after 72 h of treatment 0.9 and 1.1,respectively. moreover,5 μm dioxol significantly reduced the expression of the abcb1 gene in mdrcells by around 30%,and also decreased the level of p-gp protein. compared to untreated control cells,dioxoltreatment resulted in a significant p-gp decrease (30% in ccrf-adr5000 and 50% in ccrf-vcr1000),that was detected by western blot and confirmed by flow cytometry analysis. moreover,dioxol (at 10 μm) significantly inhibited p-gp transport function by more than twofold comparing to control,untreated cells that was demonstrated using rhodamine 123-based functional test. the compound exhibited synergistic activity with abcb1 substrate - adriamycin in ccrf-vcr1000 cells,indicating partial but significant mdr reversing ability. copyright © 2011 by institute of pharmacology polish academy of sciences.