Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells - Study of structure-activity relationship
| Authors | |
|---|---|
| Year of publication | 2009 |
| Type | Article in Periodical |
| Magazine / Source | Toxicology in Vitro |
| MU Faculty or unit | |
| Citation | |
| Web | http://www.sciencedirect.com/ |
| Field | Botany |
| Keywords | COR-L23/R; cytotoxicity; doxorubicin; dibenzocyclooctadiene lignans; multidrug resistance; MRP protein |
| Description | A panel of nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gama-schizandrin and wuweizisu C was examined for their effect on multidrug resistance, as well as their anti-proliferative activities. COR-L23/R, a multidrug-resistant sub-line, which has been reported to over-express multidrug resistance-associated protein (MRP1), was used for the experiments together with its parent cell line COR-L23 (human lung cell carcinoma). We found that lignans deoxyschizandrin and gama-schizandrin at relatively non-toxic concentrations restored the cytotoxic action of doxorubicin to COR-L23/R cells. Deoxyschizandrin and 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 deoxyschizandrin and 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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