title: Gambogic acid potentiates clopidogrel-induced apoptosis and attenuates irinotecan-induced apoptosis through down-regulating human carboxylesterase 1 and -2.
abstract: 1. In this study, we report that gambogic acid (GA), a promising anticancer agent, potentiates clopidogrel-induced apoptosis and attenuates CPT-11-induced apoptosis by down-regulating human carboxylesterase (CES) 1 and -2 via ERK and p38 MAPK pathway activation, which provides a molecular explanation linking the effect of drug combination directly to the decreased capacity of hydrolytic biotransformation. 2. The expression levels of CES1 and CES2 decreased significantly in a concentration- and time-dependent manner in response to GA in Huh7 and HepG2 cells; hydrolytic activity was also reduced. 3. The results showed that pretreatment with GA potentiated clopidogrel-induced apoptosis by down-regulating CES1. Moreover, the GA-mediated repression of CES2 attenuated CPT-11-induced apoptosis. 4. Furthermore, the ERK and p38 MAPK pathways were involved in the GA-mediated down-regulation of CES1 and CES2. 5. Taken together, our data suggest that GA is a potent repressor of CES1 and CES2 and that combination with GA will affect the metabolism of drugs containing ester bonds.
authors.affiliation: a Department of Pharmacology , Nanjing Medical University , Nanjing , P.R. China .
authors.forename: Rui
authors.initials: R
authors.lastname: Ning
authors.affiliation: b Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University , Nanjing , P.R. China .
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Wang
authors.affiliation: a Department of Pharmacology , Nanjing Medical University , Nanjing , P.R. China .
authors.forename: Yun-Ran
authors.initials: YR
authors.lastname: Zhan
authors.affiliation: c Department of Pharmacology , Emory University School of Medicine , Atlanta , GA , USA , and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Qi
authors.affiliation: d Department of Natural Medicinal Chemistry , China Pharmaceutical University , Nanjing , P.R. China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: a Department of Pharmacology , Nanjing Medical University , Nanjing , P.R. China .
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: b Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University , Nanjing , P.R. China .
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.affiliation: a Department of Pharmacology , Nanjing Medical University , Nanjing , P.R. China .
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: a Department of Pharmacology , Nanjing Medical University , Nanjing , P.R. China .
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives / Q000633:toxicity; D043182:Carboxylesterase / Q000378:metabolism*; D000077144:Clopidogrel; D015536:Down-Regulation; D000077146:Irinotecan; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; D000077146:Irinotecan; C052659:gambogic acid; D000077144:Clopidogrel; D043182:Carboxylesterase; D013988:Ticlopidine; D002166:Camptothecin
keywords: CES1; CES2; ERK; gambogic acid; p38