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Marine sponge-derived sipholane triterpenoids reverse P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.

Abstract
Previously, we reported sipholenol A, a sipholane triterpenoid from the Red Sea sponge Callyspongia siphonella, as a potent reversal of multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). Through extensive screening of several related sipholane triterpenoids that have been isolated from the same sponge, we identified sipholenone E, sipholenol L and siphonellinol D as potent reversals of MDR in cancer cells. These compounds enhanced the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine and paclitaxel, and significantly reversed the MDR-phenotype in P-gp-overexpressing MDR cancer cells KB-C2 in a dose-dependent manner. Moreover, these three sipholanes had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MRP1 (ABCC1) or MRP7 (ABCC10) or breast cancer resistance protein (BCRP/ABCG2). All three sipholanes (IC(50) >50 μM) were not toxic to all the cell lines that were used. [(3)H]-Paclitaxel accumulation and efflux studies demonstrated that all three triterpenoids time-dependently increased the intracellular accumulation of [(3)H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. Sipholanes also inhibited calcein-AM transport from P-gp-overexpressing cells. The Western blot analysis revealed that these three triterpenoids did not alter the expression of P-gp. However, they stimulated P-gp ATPase activity in a concentration-dependent manner and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. In silico molecular docking aided the virtual identification of ligand binding sites of these compounds. In conclusion, sipholane triterpenoids efficiently inhibit the function of P-gp through direct interactions and may represent potential reversal agents for the treatment of MDR.
AuthorsIoana Abraham, Sandeep Jain, Chung-Pu Wu, Mohammad A Khanfar, Yehong Kuang, Chun-Ling Dai, Zhi Shi, Xiang Chen, Liwu Fu, Suresh V Ambudkar, Khalid El Sayed, Zhe-Sheng Chen
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 80 Issue 10 Pg. 1497-506 (Nov 15 2010) ISSN: 1873-2968 [Electronic] England
PMID20696137 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier Inc. All rights reserved.
Chemical References
  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Ligands
Topics
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, metabolism)
  • Animals
  • Antineoplastic Agents (isolation & purification, metabolism, pharmacology)
  • Binding Sites
  • Callyspongia (chemistry)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Drug Resistance, Multiple (drug effects)
  • Drug Resistance, Neoplasm (drug effects)
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Immunoblotting
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Binding

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