title: Esters of the marine-derived triterpene sipholenol A reverse P-GP-mediated drug resistance.
abstract: 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.
authors: Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450003, Henan, China. zhangycqh@yahoo.com.
authors: Yongchao
authors: Y
authors: Zhang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. helloyunyun@live.com.
authors: Yun-Kai
authors: YK
authors: Zhang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. yijun.wang11@my.stjohns.edu.
authors: Yi-Jun
authors: YJ
authors: Wang
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. sgvispute@gmail.com.
authors: Saurabh G
authors: SG
authors: Vispute
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. sandeep1602@gmail.com.
authors: Sandeep
authors: S
authors: Jain
authors: Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, New Brunswick, NJ 08901, USA. m.and.m.rox.my.sox@gmail.com.
authors: Yangmin
authors: Y
authors: Chen
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. jessblue67@gmail.com.
authors: Jessalyn
authors: J
authors: Li
authors: Department of Natural Products, Faculty of Pharmacy, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. dyoussef@kau.edu.sa.
authors: Diaa T A
authors: DT
authors: Youssef
authors: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA. elsayed@ulm.edu.
authors: Khalid A
authors: KA
authors: El Sayed
authors: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. chenz@stjohns.edu.
authors: Zhe-Sheng
authors: ZS
authors: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D065567:Absorption, Physiological / Q000187:drug effects; D000085:Acetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000819:agonists* / Q000494:pharmacology; D001665:Binding Sites; D047128:Callyspongia / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004951:Esterification; D057809:HEK293 Cells; D006801:Humans; D007539:Isonicotinic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D017239:Paclitaxel / Q000819:agonists* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000085:Acetates; D000972:Antineoplastic Agents, Phytogenic; D007539:Isonicotinic Acids; D011994:Recombinant Proteins; D014315:Triterpenes; C523549:sipholenol A; D017239:Paclitaxel