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

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, s...

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Published in:Cancer science 2007-09, Vol.98 (9), p.1373-1380
Main Authors: Shi, Zhi, Jain, Sandeep, Kim, In‐Wha, Peng, Xing‐Xiang, Abraham, Ioana, Youssef, Diaa T.A., Fu, Li‐Wu, El Sayed, Khalid, Ambudkar, Suresh V., Chen, Zhe‐Sheng
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Language:English
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Summary: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 (IC50 > 50 µM) 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 [3H]‐paclitaxel demonstrated that sipholenol A time‐dependently increased the intracellular accumulation of [3H]‐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 [125I]‐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. (Cancer Sci 2007; 98: 1373–1380)
ISSN:1347-9032
1349-7006
DOI:10.1111/j.1349-7006.2007.00554.x