Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer

Abstract

The roles of glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 2 (GSTM2) and glutathione S-transferase alpha 1 (GSTA1) in cisplatin (DDP)-resistance of solid cancer cells (A549/DDP, SKOV3/DDP and SGC7901/DDP) were compared following expression downregulation with small interfering RNAs (siRNAs). DDP cytotoxicity was reflected by its half maximal inhibition concentration (IC 50 ) calculated from data using a Cell Counting Kit-8 assay; cell apoptosis was examined using flow cytometry and Hoechst 33342 staining. Higher activities of GST were detected in the cytosol of DDP-resistant cells, compared with those in the parental DDP-susceptible cells. The silencing efficacy of each positive siRNA was supported by western blot analysis. GSTP1 silencing resulted in a 4-fold sensitization of SGC7901/DDP cells to DDP cytotoxicity, but negligible sensitization of SKOV3/DDP and A549/DDP cells. GSTM2 silencing sensitized SKOV3/DDP and A549/DDP cells to DDP cytotoxicity by ~2-fold, but did not sensitize SGC7901/DDP cells. Notably, GSTA1 silencing enhanced DDP cytotoxicity in SGC7901/DDP cells by 6-fold, in A549/DDP cells by 5-fold and in SKOV3/DDP cells by 2-fold. The combined actions of positive siRNAs and DDP increased the percentages of apoptotic cells in the DDP-resistant solid cancer cells compared with the combined actions of DDP and the negative siRNAs. The present findings indicated that GSTA1 is a predominant GST isozyme associated with DDP resistance of SGC7901/DDP, A549/DDP and SKOV3/DDP cells; GSTA1-specific inhibitors may be general sensitizers of SGC7901/DDP, A549/DDP and SKOV3/DDP cells to DDP cytotoxicity through the promotion of cell apoptosis.

A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1

“…Thus, the proposition that the role of GST P1-1 in cis -DDP inactivation is due to enzymatic conjugation of GSH with cis- DDP is not supported (14, 44, 45), but the GST P1-1–induced resistance to cis -DDP–induced cell death is instead mediated by one of its other functions (40). Note that it has also been suggested that the isoenzyme alpha 1 (GST A1-1) is also involved in cis -DDP resistance, but the biochemical mechanism underlying GST A1-1–mediated cis -DDP resistance has not been clarified (46).…”

Mechanisms of Anticancer Drug Resistance in Hepatoblastoma

“…Concerning MOC-2, the group of enzymes glutathione S-transferases (GSTs) can play a role in cisplatin chemoresistance, since a higher conjugation of platinum derivatives with glutathione produces more inactive metabolites and a reduction of intracellular concentrations of active drugs [23]. Higher activity of GST alpha 1 (GST1A) has been associated with the resistance to cisplatin in several solid tumors [36], however, low expression of GST1A was found in HB specimens [29]. Upregulation of GSTmu (GSTM) was observed in two thirds of HB xenografts after treatment with cisplatin [37].…”

Quinacrine inhibits GSTA1 activity and induces apoptosis through G1/S arrest and generation of ROS in human non-small cell lung cancer cell lines

“…GSTA1 is known to inactivate alkylating drugs such as Busulfran, Brostallicin, Carboplatin, cyclophosphamides and anthracycline drugs such as doxorubucin etc. through glutathione conjugation [32,33]. In addition to its catalytic activity, GSTA is also involved in preventing JNK1 induced apoptosis in cases of oxidative stress and cytokine mediated inflammatory response.…”