Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

Abstract

Multidrug resistance in cancer cells is often associated with an elevation in the concentration of glutathione ( GSH ) and the expression of -glutamylcysteine synthetase ( -GCS ), a rate -limiting enzyme for GSH. We constructed a hammerhead ribozyme against a -GCS heavy subunit ( -GCSh ) mRNA transcript and transfected it to human colonic cancer cells ( HCT8DDP ) resistant to cisplatin ( CDDP ). The effect of the ribozyme transfection on the drug resistance of cancer cells was studied.

γ-Glutamylcysteine Synthetase Mediates the c-Myc-Dependent Response to Antineoplastic Agents in Melanoma Cells

“…Our results are in agreement with data demonstrating that most c-Myc phenotypes can be explained by the activation/repression of the target genes set under its control (Iida et al, 2001;Zeller et al, 2003). In the context of drug response, Park et al (2002) demonstrated that overexpression of c-Myc can promote survival through activation of the ornithine decarbox- The role of ␥-GCS on the c-Myc-dependent drug response is not limited to CDDP.…”

17β-Estradiol Protects against Oxidative Stress-induced Cell Death through the Glutathione/Glutaredoxin-dependent Redox Regulation of Akt in Myocardiac H9c2 Cells

“…Northern Blot Analysis-A 764-bp DNA fragment (bp 865-1628) of fulllength ␥-GCS heavy subunit cDNA was obtained by digestion with PstI (29). The probes were radiolabeled with 32 P using a random primer labeling kit (Takara Biomedicals, Shiga, Japan).…”

Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

“…Based on prior reports indicating that some of the ABC transporters may be implicated in the Pt drug accumulation defect found in resistant cells [22,23], we compared the level of expression of MRP1 -MRP4 and BCRP in the IGROV-1 and IGROV-1/OHP cells ( Figure 2). The MRP2, MRP3 and BCRP were not expressed in either cell type.…”

“…Cells that have acquired resistance to cisplatin often have impaired drug uptake [15] and this has been linked to altered expression of genes involving copper metabolism [16][17][18][19][20][21]. Additional studies have implicated members of the ATP binding cassette (ABC) family of transporters such as Multidrug resistance associated protein (MRP) 2 and MRP1 in the accumulation defects found in cisplatin-resistant cells [22,23]. Based on similarity to other members of this family [24], it is likely that other ABC transporters are involved in regulating sensitivity to the Pt compounds.…”