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Mar. Drugs 2015, 13(4), 2267-2286;

Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance

Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901, USA
Department of Natural Products, Faculty of Pharmacy, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
Current Address: William A. Shine Great Neck South High School, 341 Lakeville Road, Great Neck, NY 11020, USA.
Author to whom correspondence should be addressed.
Academic Editors: Friedemann Honecker and Sergey A. Dyshlovoy
Received: 2 February 2015 / Revised: 10 March 2015 / Accepted: 25 March 2015 / Published: 14 April 2015
(This article belongs to the Collection Marine Compounds and Cancer)
Full-Text   |   PDF [1071 KB, uploaded 14 April 2015]   |  


Our previous studies showed that several sipholane triterpenes, sipholenol A, sipholenone E, sipholenol L and siphonellinol D, have potent reversal effect for multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp/ABCB1). Through comparison of cytotoxicity towards sensitive and multi-drug resistant cell lines, we identified that the semisynthetic esters sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate potently reversed P-gp-mediated MDR but had no effect on MRP1/ABCC1 and BCRP/ABCG2-mediated MDR. The results from [3H]-paclitaxel accumulation and efflux studies suggested that these two triterpenoids were able to increase the intracellular accumulation of paclitaxel by inhibiting its active efflux. In addition, western blot analysis revealed that these two compounds did not alter the expression levels of P-gp when treated up to 72 h. These sipholenol derivatives also stimulated the ATPase activity of P-gp membranes, which suggested that they might be substrates of P-gp. Moreover, in silico molecular docking studies revealed the virtual binding modes of these two compounds into human homology model of P-gp. In conclusion, sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate efficiently inhibit the P-gp and may represent potential reversal agents for the treatment of multidrug resistant cancers. View Full-Text
Keywords: sipholenol A; ABC transporter; multidrug resistance; P-gp/ABCB1; BCRP/ABCG2; MRP1/ABCC1; marine natural products sipholenol A; ABC transporter; multidrug resistance; P-gp/ABCB1; BCRP/ABCG2; MRP1/ABCC1; marine natural products

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Zhang, Y.; Zhang, Y.-K.; Wang, Y.-J.; Vispute, S.G.; Jain, S.; Chen, Y.; Li, J.; Youssef, D.T.A.; Sayed, K.A.E.; Chen, Z.-S. Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance. Mar. Drugs 2015, 13, 2267-2286.

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