Publication details

Deoxyschizandrin and gama-schizandrin restore the cytotoxic action of doxorubicin in multi-drug resistant lung cancer cells COR-L23/R

Authors

SLANINA Jiří ADÁMKOVÁ Lenka KOUBÍKOVÁ Ludmila HAMMEROVÁ Jindřiška SLANINOVÁ Iva

Year of publication 2009
Type Article in Proceedings
Conference Book of Abstract of Conference of Functional Molecules from Natural Sources
MU Faculty or unit

Faculty of Medicine

Citation
Field Morphological specializations and cytology
Keywords Schisandra chinensis; dibenzocyclooctadiene lignans; multidrug resistance; MDR; MRP; cell cycle; cytotoxicity
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.
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