PMID- 17666793
OWN - NLM
STAT- MEDLINE
DCOM- 20070921
LR  - 20190720
IS  - 0918-6158 (Print)
IS  - 0918-6158 (Linking)
VI  - 30
IP  - 8
DP  - 2007 Aug
TI  - Irinotecan-induced apoptosis is inhibited by increased P-glycoprotein expression 
      and decreased p53 in human hepatocellular carcinoma cells.
PG  - 1400-6
AB  - Irinotecan, a DNA topoisomerase I inhibitor, is widely used in cancer 
      chemotherapy. However, little is known of the mechanisms of its antitumor effects 
      and the development of drug resistance in human hepatocellular carcinoma (HCC). 
      In this study, we investigated the effects of short-term culture with SN-38, the 
      active metabolite of irinotecan, on apoptosis in Huh7 cells. The cells were 
      cultured with SN-38 for 24, 72, and 120 h, and apoptosis was determined using the 
      terminal dUTP nick-end labeling (TUNEL) assay. The expressions of p53, 
      apoptosis-related proteins, and P-glycoprotein (P-gp), a protein conferring the 
      multidrug-resistant phenotype, were analyzed using Western blotting. Induced 
      expression of P-gp was detected using fluorescence microscopy. SN-38 
      significantly induced apoptosis in Huh7 cells at 24 h. SN-38 also increased the 
      expression of p53, Bax, and caspase-9 and decreased Bcl-xL expression in Huh7 
      cells. SN-38 decreased p53 expression and increased P-gp expression after 120 h, 
      resulting in inhibition of apoptosis. This inhibition was reversed by the 
      addition of verapamil to the culture medium during 120 h incubation. 
      SN-38-induced P-gp expression was additionally enhanced by p53 decoy 
      oligodeoxynucleotide. The changes in P-gp expression were directly moderated by 
      p53 gene downregulation, suggesting that it plays a role in the mechanism of drug 
      resistance. These results suggest that the accumulation of irinotecan in HCC 
      leads to the development of drug resistance.
FAU - Takeba, Yuko
AU  - Takeba Y
AD  - Department of Pharmacology, St. Marianna University School of Medicine, 2-16-1 
      Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. yakuri@marianna-u.ac.jp
FAU - Sekine, Susumu
AU  - Sekine S
FAU - Kumai, Toshio
AU  - Kumai T
FAU - Matsumoto, Naoki
AU  - Matsumoto N
FAU - Nakaya, Sachiko
AU  - Nakaya S
FAU - Tsuzuki, Yashimitsu
AU  - Tsuzuki Y
FAU - Yanagida, Yohei
AU  - Yanagida Y
FAU - Nakano, Hiroshi
AU  - Nakano H
FAU - Asakura, Takeshi
AU  - Asakura T
FAU - Ohtsubo, Takehito
AU  - Ohtsubo T
FAU - Kobayashi, Shinichi
AU  - Kobayashi S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Oligonucleotides)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 7673326042 (Irinotecan)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis/physiology
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Blotting, Western
MH  - Camptothecin/*analogs & derivatives/pharmacology
MH  - Carcinoma, Hepatocellular/*metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Irinotecan
MH  - Liver Neoplasms/*metabolism
MH  - Microscopy, Fluorescence
MH  - Oligonucleotides/pharmacology
MH  - RNA, Neoplasm/biosynthesis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Suppressor Protein p53/*biosynthesis/physiology
EDAT- 2007/08/02 09:00
MHDA- 2007/09/22 09:00
CRDT- 2007/08/02 09:00
PHST- 2007/08/02 09:00 [pubmed]
PHST- 2007/09/22 09:00 [medline]
PHST- 2007/08/02 09:00 [entrez]
AID - JST.JSTAGE/bpb/30.1400 [pii]
AID - 10.1248/bpb.30.1400 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2007 Aug;30(8):1400-6. doi: 10.1248/bpb.30.1400.