Document Detail

Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.
MedLine Citation:
PMID:  20724170     Owner:  NLM     Status:  MEDLINE    
P-glycoprotein (P-gp) is known to mediate multidrug resistance (MDR) by acting as an efflux pump to actively transport chemotherapeutic agents out of carcinoma cells. Inhibition of P-gp function may represent one of the strategies to reverse MDR. We have previously reported that marchantin C (MC), a macrocyclic bisbibenzyl compound from liverworts, exerts anti-tumor activity as an antimitotic agent. This study was designed to evaluate the possible modulatory effect of MC and its three synthetic derivatives (MC1, MC2 and MC3) on P-gp in VCR-resistant KB/VCR cells. Results of the cytotoxicity assay revealed that MC was the most potent inhibitor of cell proliferation in both KB and KB/VCR cells among these four compounds, while the three MC-derived chemicals had little anti-proliferative activity under the same condition. However, in P-gp-expressing MDR cells, analysis of potency of these compounds in enhancing cytotoxicity of VCR led to the identification of MC2 as a more effective chemical on reversal of resistance. Further study showed that MC2 was able to reduce efflux of rhodamine-123, and in turn, increase the accumulation of rhodamine-123 and adriamycin in KB/VCR cells, indicating that MC2 re-sensitized cells to VCR by inhibition of the P-gp transport activity. In addition, the combination of MC2 and VCR at a concentration that does not inhibit cell growth resulted in an induction of apoptosis in KB/VCR cells. These results suggest that MC2, as a novel and effective inhibitor of P-gp, may find potential application as an adjunctive agent with conventional chemotherapeutic drugs to reverse MDR in P-gp overexpressing cancer cells.
Guang-min Xi; Bin Sun; Hui-Hui Jiang; Feng Kong; Hui-qing Yuan; Hong-xiang Lou
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-29
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  18     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-06     Completed Date:  2010-12-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  6725-33     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
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MeSH Terms
Antineoplastic Agents / chemical synthesis,  chemistry,  toxicity*
Bibenzyls / chemical synthesis,  chemistry*,  toxicity
Catechols / chemical synthesis,  chemistry*,  toxicity
Cell Line, Tumor
Doxorubicin / metabolism
Drug Resistance, Neoplasm / drug effects
Ethers, Cyclic / chemical synthesis,  chemistry*,  toxicity
P-Glycoprotein / antagonists & inhibitors*,  metabolism
Phenyl Ethers / chemical synthesis,  chemistry*,  toxicity
Rhodamine 123 / metabolism
Stilbenes / chemical synthesis,  chemistry*,  toxicity
Vincristine / pharmacology
Reg. No./Substance:
0/Antineoplastic Agents; 0/Bibenzyls; 0/Catechols; 0/Ethers, Cyclic; 0/P-Glycoprotein; 0/Phenyl Ethers; 0/Stilbenes; 0/marchantin C; 23214-92-8/Doxorubicin; 57-22-7/Vincristine; 62669-70-9/Rhodamine 123

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