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Bisbibenzyl derivatives sensitize vincristine-resistant KB/VCR cells to chemotherapeutic agents by retarding P-gp activity.

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.
AuthorsGuang-min Xi, Bin Sun, Hui-Hui Jiang, Feng Kong, Hui-qing Yuan, Hong-xiang Lou
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 18 Pg. 6725-33 (Sep 15 2010) ISSN: 1464-3391 [Electronic] England
PMID20724170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (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
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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