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Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells.

Abstract
Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. Sipholenol A (IC(50) > 50 microM) is not toxic to all the cell lines that were used, regardless of their membrane transporter status. Accumulation and efflux studies with the P-gp substrate [(3)H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [(3)H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not alter the expression of P-gp after treating KB-C2 and KB-V1 cells for 36 h and 72 h. However, it efficaciously stimulated the activity of ATPase of P-gp and inhibited the photolabeling of this transporter with its transport substrate [(125)I]-iodoarylazidoprazosin. Overall, the present results indicate that sipholenol A efficiently inhibits the function of P-gp through direct interactions, and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp-overexpressing tumors.
AuthorsZhi Shi, Sandeep Jain, In-Wha Kim, Xing-Xiang Peng, Ioana Abraham, Diaa T A Youssef, Li-Wu Fu, Khalid El Sayed, Suresh V Ambudkar, Zhe-Sheng Chen
JournalCancer science (Cancer Sci) Vol. 98 Issue 9 Pg. 1373-80 (Sep 2007) ISSN: 1347-9032 [Print] England
PMID17640301 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents, Phytogenic
  • Azides
  • Iodine Radioisotopes
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Photoaffinity Labels
  • Triterpenes
  • sipholenol A
  • azidoprazosin
  • Prazosin
  • multidrug resistance-associated protein 1
Topics
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism, physiology)
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (biosynthesis)
  • Animals
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Azides (metabolism)
  • Callyspongia
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm (drug effects)
  • Humans
  • Iodine Radioisotopes (metabolism)
  • KB Cells
  • Multidrug Resistance-Associated Proteins (biosynthesis)
  • Neoplasm Proteins (biosynthesis)
  • Photoaffinity Labels (metabolism)
  • Prazosin (analogs & derivatives, metabolism)
  • Triterpenes (isolation & purification, pharmacology)

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