Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells--study of structure-activity relationship.
A panel of nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gamma-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 gamma-schizandrin at relatively non-toxic concentrations restored the cytotoxic action of doxorubicin to COR-L23/R cells. Deoxyschizandrin and gamma-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 gamma-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.
Slaninová
I
I
Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic. islaninova@seznam.cz
Brezinová
L
L
Koubíková
L
L
Slanina
J
J
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D034242:Cyclooctanes; D017705:Lignans; C510994:dibenzocyclooctadiene lignan; D004317:Doxorubicin