RRC ID 38448
Author Okumura M, Iwakiri T, Takagi A, Hirabara Y, Kawano Y, Arimori K.
Title Hepatocyte growth factor suppresses the anticancer effect of irinotecan by decreasing the level of active metabolite in HepG2 cells.
Journal Biochem Pharmacol
Abstract In the liver, carboxylesterase (CES) converts irinotecan (CPT-11) to its active metabolite SN-38, which exerts anticancer effects. SN-38 is metabolized to an inactive metabolite SN-38 glucuronide by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1). Therefore, single nucleotide polymorphisms (SNPs) of the UGT1A1 gene are responsible for the severe adverse effects associated with the disruption of SN-38 metabolism. However, despite having SNPs of the UGT1A1 gene, many patients metabolize SN-38 sufficiently to avoid severe adverse effects. Among these patients, we found individuals with elevated serum concentrations of hepatocyte growth factor (HGF). The aim of this study was to evaluate whether HGF alters the metabolism of CPT-11, resulting in a reduction in the anticancer effect of CPT11. The cytotoxicity of CPT-11 and SN-38 was evaluated in HepG2 cells pretreated with HGF. Furthermore, we explored the level of expression and mechanisms of activity of CES and UGT1A1. HGF suppressed the cytotoxicity of CPT-11 by decreasing intracellular SN-38 levels that resulted from a decrease in CES2 and an increase in UGT1A1. Furthermore, this HGF-induced suppression was improved by pretreatment with an inhibitor of HGF receptor c-Met, and the improvement was synergistically potentiated by epidermal growth factor receptor (EGFR) inhibitors. Moreover, HGF induced phosphorylation of signal transducer and activator of transcription 3 and transactivated EGFR. These results suggest that HGF is a possible causative agent of acquired clinical resistance in chemotherapy with CPT-11 and could be useful as a predictor of clinical resistance. Additional treatment using c-Met and/or EGFR inhibitors could be a novel strategy to overcome resistance.
Volume 82(11)
Pages 1720-30
Published 2011-12-1
DOI 10.1016/j.bcp.2011.07.095
PII S0006-2952(11)00612-5
PMID 21840303
MeSH Antineoplastic Agents / metabolism Antineoplastic Agents / pharmacology* Camptothecin / analogs & derivatives* Camptothecin / metabolism Camptothecin / pharmacology Carboxylesterase / metabolism Cell Proliferation Drug Resistance, Neoplasm Drug Synergism Epidermal Growth Factor / pharmacology ErbB Receptors / genetics Glucuronosyltransferase / metabolism Hep G2 Cells Hepatocyte Growth Factor / pharmacology Hepatocyte Growth Factor / physiology* Humans Irinotecan Phosphorylation Proto-Oncogene Proteins c-met / genetics Receptor Protein-Tyrosine Kinases / antagonists & inhibitors STAT3 Transcription Factor / metabolism Signal Transduction Transcriptional Activation
IF 4.96
Times Cited 4
Human and Animal Cells