| Description |
Dibenzo[a,c]cyclooctadiene lignans are natural products originated from Schisandra chinensis (Schisandraceae), 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 These lignans 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. A panel of nine dibenzo[a,c]cyclooctadiene lignans (schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gammaschizandrin and wuweizisu C), isolated by us from seeds of S. chinensis, was examined for their effect on multidrug resistance, as well as their anti-proliferative and pro-apoptotic activities. CORL23/R, a multidrug resistant subline overexpressing multidrug resistanceassociated protein 1 (MRP1) together with its parent cell line CORL23 (human lung cell carcinoma) and HL60 (human promyelocytic leukemia) cell lines were used. We found that deoxyschizandrin and gammaschizandrin at relatively nontoxic concentrations restored the cytotoxic action of doxorubicin, a MRP1 substrate, to CORL23/R cells. Moreover, deoxyschizandrin and gammaschizandrin showed the greatest ability to enhance the accumulation of doxorubicin in drug resistant cells. Lignans alone had no effect on the cell cycle, however, in combination with subtoxic doses of doxorubicin, cell were arrested in the G2/M phase, which is typical for doxorubicin at toxic doses. Our results suggest that deoxyschizandrin and gammaschizandrin potentiate the effect of doxorubicin in doxorubicin resistant lung cancer cells by increasing the accumulation of doxorubicin inside the cells. The common structural feature of both active lignans and missing from the less active or inactive lignans is the Rbiaryl configuration and the absence of a hydroxy group at C8. Unlike the reversion effect, the cytotoxicity of lignans with either the Rbiaryl or Sbiaryl configurations was approximately same.
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