| Description |
Schisandra chinensis (Schisandraceae) 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. 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. 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 expelled from the resistant cells. We found that two lignans, R-(+)-deoxyschizandrin and R,S-( )-gama-schizandrin at relatively non-toxic concentrations restored the cytotoxic action of doxorubicin, a MRP1 substrate, to COR-L23/R cells. Moreover, R-(+)-deoxyschizandrin and R,S-( )-gama-schizandrin also 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-( )-gama-schizandrin potentiate the cytotoxic effect of doxorubicin in doxorubicin resistant lung cancer cells COR-L23/R by increasing the accumulation of doxorubicin inside the cells. The common structural feature of both active lignans is the R-biaryl configuration and the absence of a hydroxy group at C-8. 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.
|
