| Description |
Cancer multidrug resistance is one of the major causes of failure of chemotherapy. Over expression of the ATP binding cassette members, particularly P glycoprotein (Pgp, ABCB1) and family of multidrug resistance associated proteins (MRP1 MRP9) exporting drugs out of the cells, are responsible for most cases of clinical cancer multidrug resistance (Filipits, 2004; Yu et a., 2007). One of the current challenges of anticancer therapy research is uncovering compounds, which can act as MDR modulators and co-administer them with anticancer drugs to make treatment more effective and to minimize drug side effects. Recently, dibenzocyclooctadiene lignans have been discussed as compounds that have the potential to overcome multidrug resistance (Sun et al., 2007, Pan et al., 2005). These lignans originated from fruit of Schisandra chinensis (Schisandraceae) that is a well known medicinal plant in traditional Chinese medicine. The fruits and seeds have been used for centuries as a tonic and antitussive. Many studies have indicated that the active ingredients are lignans possessing an unusual structure derived from dibenzo[a,c]cyclooctadiene, which have been shown to possess a broad range of biological effects, including hepatoprotective and antiviral properties. Recently, dibenzocyclooctadiene lignans have been discussed as compounds that are able to overcome multidrug resistance. In this study, nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gama-schizandrin and wuweizisu C, isolated from seeds of Schisandra chinensis, were examined for their effect on multidrug resistance, as well as their anti proliferative activities. COR L23/R, a multidrug-resistant sub-line over-expressing multidrug resistance-associated proteins 1 and 2 (MRP1 and MRP2) and its parent cell line COR L23 (human lung cell carcinoma) were used in these experiments. Our observations showed that COR L23/R was nearly hundred times more resistant to doxorubicin than the parental line COR-L23; although both cell lines were similarly sensitive to lignans treatment, indicating that the lignans are not exported from the resistant cells. We found out that two lignans, R(+)deoxyschizandrin and R,S( )gamaschizandrin at relatively non toxic concentrations restored the cytotoxic action of doxorubicin, a MRP1 substrate, to COR L23/R cells. Using doxorubicin accumulation assay we demonstrated that R (+) deoxyschizandrin and R,S ( )gamaschizandrin significantly enhanced the accumulation of doxorubicin in drug resistant cells. Both lignans alone 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, which is typical for toxic doses of doxorubicin. Our results suggest that R(+)deoxyschizandrin and R,S( )gamaschizandrin potentiate the cytotoxic effect of doxorubicin in doxorubicin resistant lung cancer cells COR L23/R by increasing the accumulation of doxorubicin inside the cells. In the structural point of view, we can conclude that the common structural feature of both active lignans is the Rbiaryl configuration and the absence of a hydroxy group at C8. Unlike the reversal effect, the cytotoxicity of lignans with the R biaryl configuration was similar to that observed for lignans with the S biaryl configuration.
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