PMID- 11500053
OWN - NLM
STAT- MEDLINE
DCOM- 20010920
LR  - 20161124
IS  - 0006-291X (Print)
IS  - 0006-291X (Linking)
VI  - 286
IP  - 2
DP  - 2001 Aug 17
TI  - Reversal of cisplatin and multidrug resistance by ribozyme-mediated glutathione 
      suppression.
PG  - 406-13
AB  - gamma-Glutamylcysteine synthetase (gamma-GCS) is a key enzyme in glutathione 
      (GSH) synthesis, and is thought to play a significant role in intracellular 
      detoxification, especially of anticancer drugs. Increased levels of GSH are 
      commonly found in the drug-resistant human cancer cells. We designed a hammerhead 
      ribozyme against gamma-GCS mRNA (anti-gamma-GCS Rz), which specifically 
      down-regulated gamma-GCS gene expression in the HCT-8 human colon cancer cell 
      line. The aim of this study was to reverse the cisplatin and multidrug resistance 
      for anticancer drugs. The cisplatin-resistant HCT-8 cells (HCT-8DDP cells) 
      overexpressed MRP and MDR1 genes, and showed resistance to not only cisplatin 
      (CDDP), but also doxorubicin (DOX) and etoposide (VP-16). We transfected a vector 
      expressing anti-gamma-GCS Rz into the HCT-8DDP cells (HCT-8DDP/Rz). The 
      anti-gamma-GCS Rz significantly suppressed MRP and MDR, and altered anticancer 
      drug resistance. The HCT-8DDP/Rz cells were more sensitive to CDDP, DOX and VP-16 
      by 1.8-, 4.9-, and 1.5-fold, respectively, compared to HCT-8DDP cells. The 
      anti-gamma-GCS Rz significantly down-regulated gamma-GCS gene expression as well 
      as MRP/MDR1 expression, and reversed resistance to CDDP, DOX and VP-16. These 
      results suggested that gamma-GCS plays an important role in both cisplatin and 
      multidrug resistance in human cancer cells.
CI  - Copyright 2001 Academic Press.
FAU - Nagata, J
AU  - Nagata J
AD  - Department of Pathology, Tokai University School of Medicine, Bohseidai, 
      Kanagawa, 259-1193, Japan.
FAU - Kijima, H
AU  - Kijima H
FAU - Hatanaka, H
AU  - Hatanaka H
FAU - Asai, S
AU  - Asai S
FAU - Miyachi, H
AU  - Miyachi H
FAU - Takagi, A
AU  - Takagi A
FAU - Miwa, T
AU  - Miwa T
FAU - Mine, T
AU  - Mine T
FAU - Yamazaki, H
AU  - Yamazaki H
FAU - Nakamura, M
AU  - Nakamura M
FAU - Kondo, T
AU  - Kondo T
FAU - Scanlon, K J
AU  - Scanlon KJ
FAU - Ueyama, Y
AU  - Ueyama Y
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antineoplastic Agents)
RN  - 0 (RNA, Catalytic)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - EUY85H477I (thiazolyl blue)
RN  - GAN16C9B8O (Glutathione)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Cisplatin/*therapeutic use
MH  - Colonic Neoplasms/genetics/metabolism/*therapy
MH  - Drug Resistance, Multiple
MH  - Drug Resistance, Neoplasm
MH  - Glutamate-Cysteine Ligase/genetics
MH  - Glutathione/*antagonists & inhibitors
MH  - Humans
MH  - RNA, Catalytic/*therapeutic use
MH  - RNA, Neoplasm/biosynthesis/genetics
MH  - Tetrazolium Salts/chemistry
MH  - Thiazoles/chemistry
MH  - Tumor Cells, Cultured
EDAT- 2001/08/14 10:00
MHDA- 2001/09/21 10:01
CRDT- 2001/08/14 10:00
PHST- 2001/08/14 10:00 [pubmed]
PHST- 2001/09/21 10:01 [medline]
PHST- 2001/08/14 10:00 [entrez]
AID - S0006-291X(01)95399-9 [pii]
AID - 10.1006/bbrc.2001.5399 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2001 Aug 17;286(2):406-13. doi: 
      10.1006/bbrc.2001.5399.