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Effect of dibenzocyclooctadiene lignans on multidrug resistant promyelotic leukaemia cells

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Year of publication 2012
Type Conference abstract
MU Faculty or unit

Faculty of Medicine

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Description In this study we used multidrug resistant promyelotic leukaemia cells overexpressing MDR1 (P-glycoprotein), the most common member of ABC transporters family (HL60/ MDR). The ability to overcome multidrug resistance was examined in the panel of dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin-dicarbaldehyde, wuweizisu C, and S(-)- and R(+)-enantiomers of deoxyschizandrin, y-schizandrin and gomisin J. The lignans were isolated from Schisandra chinensis seeds or prepared semisynthetically. We observed that resistant HL60/MDR was nearly hundred times more resistant to doxorubicin than the parental line HL60; although both cell lines were similarly sensitive to lignans treatment, indicating that the lignans are not exported from the resistant cells. Using doxorubicin accumulation assay we demonstrated that all lignans significantly enhanced the accumulation of doxorubicin in drug resistant cells. The results were comparable or even higher than Verapamil used as a positive control. Comparing enantiomers of individual lignans, we observed higher effect of R(+)-y-schizandrin. On WST and PI- exclusion assay we demonstrated that the lignans enhanced cytotoxic effect of sub-toxic concentrations of doxorubicin. Deoxyschizandrin and Gomisin N were selected for further studies because of high activity in accumulation assay. Deoxyschizandrin and gomisin N had no effect on the cell cycle; however, when combined with sub-toxic doses of doxorubicin, they induced cell cycle arrest in the G2/M phase, what is typical for toxic doses of doxorubicin. The results proved the ability of DBL to overcome MDR resistance in P-glycoprotein overexpressing HL60 cell, due to the increasing doxorubicin accumulation inside the cells. DBL represents substances promising for treatment of multidrug resistant cancer.
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