Abstract |
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.
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Authors | Guang-min Xi, Bin Sun, Hui-Hui Jiang, Feng Kong, Hui-qing Yuan, Hong-xiang Lou |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 18
Issue 18
Pg. 6725-33
(Sep 15 2010)
ISSN: 1464-3391 [Electronic] England |
PMID | 20724170
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright (c) 2010 Elsevier Ltd. All rights reserved. |
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Bibenzyls
- Catechols
- Ethers, Cyclic
- Phenyl Ethers
- Stilbenes
- marchantin C
- Rhodamine 123
- Vincristine
- Doxorubicin
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(antagonists & inhibitors, metabolism)
- 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)
- Humans
- Phenyl Ethers
(chemical synthesis, chemistry, toxicity)
- Rhodamine 123
(metabolism)
- Stilbenes
(chemical synthesis, chemistry, toxicity)
- Vincristine
(pharmacology)
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