RRC ID 43029
Author Takeba Y, Kumai T, Matsumoto N, Nakaya S, Tsuzuki Y, Yanagida Y, Kobayashi S.
Title Irinotecan activates p53 with its active metabolite, resulting in human hepatocellular carcinoma apoptosis.
Journal J Pharmacol Sci
Abstract The topoisomerase I inhibitor irinotecan is widely used in anticancer therapy, although the detailed mechanism is still unclear. We investigated the apoptotic mechanisms of irinotecan in human hepatocellular carcinoma (HCC) cell lines (Huh7). SN-38 caused a significant decrease in cell proliferation and induced apoptosis in Huh7 cells and HepG2 cells. SN-38 significantly increased the expression of p53 protein and its phosphorylation at Ser(15) in the nucleus and apoptosis-inducing proteins Bax, caspase-9, and caspase-3, while it significantly decreased the antiapoptosis protein Bcl-xL of Huh7 cells. SN-38-induced apoptosis was recovered after p53 antisense oligodeoxynucleotide (AS ODN) pretreatment, while Huh7 cells were precultured with p53 AS ODN, followed by the addition of SN-38 for 24 h. Furthermore, increases in p53 DNA-binding activity were observed in the nuclei of Huh7 cells after SN-38 treatment as shown by electrophoretic mobility shift analysis. SN-38 binding motifs were detected in the proximal promoter of p53 (bases -433 to -317 and -814 to -711). These results suggest that the p53-mediated apoptosis pathway is important in the anticancer effects of irinotecan in hepatocellular carcinoma.
Volume 104(3)
Pages 232-42
Published 2007-7-1
DOI 10.1254/jphs.fp0070442
PII JST.JSTAGE/jphs/FP0070442
PMID 17609585
MeSH Antineoplastic Agents, Phytogenic / pharmacokinetics Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects* Apoptosis Regulatory Proteins / physiology Blotting, Western Camptothecin / analogs & derivatives* Camptothecin / pharmacokinetics Camptothecin / pharmacology Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Proliferation / drug effects DNA Fragmentation / drug effects DNA Probes Electrophoretic Mobility Shift Assay Humans In Situ Nick-End Labeling Irinotecan Liver Neoplasms / drug therapy* Liver Neoplasms / pathology Oligonucleotides / pharmacology Tumor Suppressor Protein p53 / metabolism*
IF 2.835
Times Cited 29
Human and Animal Cells