Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells--study of structure-activity relationship.

Abstract

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.

• Authors: I Slaninová, L Brezinová, L Koubíková, J Slanina
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 23 Issue 6 Pg. 1047-54 (Sep 2009) ISSN: 1879-3177 [Electronic] England
• PMID: 19531378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cyclooctanes
• Lignans
• dibenzocyclooctadiene lignan
• Doxorubicin

Topics

• Antibiotics, Antineoplastic (administration & dosage, metabolism, pharmacology)
• Carcinoma, Large Cell (drug therapy, metabolism)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cyclooctanes (administration & dosage, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, metabolism, pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• G2 Phase (drug effects)
• Humans
• Lignans (administration & dosage, chemistry, pharmacology)
• Lung Neoplasms (drug therapy, metabolism)
• Structure-Activity Relationship