Evidence for the Involvement of the Glutathione Pathway in Drug Resistance in AML

Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis, wild-type TP53, and vicinal thiol/disulfide status

“…13,15,42,78,79 In several cellular models, bcl proteins transfected into hematopoietic cells affected sensitivity to mitochondrial depolarization, but our data do not support the idea sometimes extrapolated from these studies that variations in total expression of bcl-2, bcl-x, or bax are responsible for clinical variability in chemoresistance. In our experiments, absolute levels of bcl-2, bax, or bcl-x did not appear to be important.…”

Sulphonamide-based bombesin prodrug analogues for glutathione transferase, useful in targeted cancer chemotherapy

“…This concept was realized by designing chimaeric sulphonamide derivatives (bombesin analogues, Fig. 2) able to undergo cleavage in tumour cells by intracellular GSTs where certain GST isoenzymes, such as hGSTA1-1, are highly expressed [11,13,14]. Selective targeting of these prodrugs to cancer tissues might be made possible if they bore a chemical moiety (e.g.…”

“…A plausible mechanism by which GSTs could contribute to drug resistance includes GST-dependent prevention of drug-induced apoptosis via direct interaction with signal transduction proteins, as suggested for GSTP1-1 [15,16] which inhibits c-Jun N-terminal kinase. It has been demonstrated that hGSTA1/A2 protein was increased in blast cells (derived from acute myeloid leukemia patients) showing resistance to doxorubicin in vitro [13], and a weak correlation was observed between GST alpha in gastric cancer tissues and cisplatin resistance (in vitro) [14]. However, more recently, it was shown that homozygous hGSTA1*B breast cancer patients treated with cyclophosphamide (plus other chemotherapeutic drugs) had a reduced death hazard during the first 5 years following diagnosis compared with homozygous hGSTA1*A individuals (hazard ratio, 0.3) [15].…”

“…This phenomenon, referred to as multi-drug resistance, has complicated attempts towards cancer therapy [12]. A possible origin for the problem appears to be an increase in the expression of total GST activity in tumour cells [13,14]. A plausible mechanism by which GSTs could contribute to drug resistance includes GST-dependent prevention of drug-induced apoptosis via direct interaction with signal transduction proteins, as suggested for GSTP1-1 [15,16] which inhibits c-Jun N-terminal kinase.…”

Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase

“…GSH conjugates are finally disposed of by excretion via the ATP-driven efflux pumps MRP-1 and MRP-2. 11,12 Overexpression of the enzymes of the GST alpha family, characterized by a high peroxidase activity, 13 has been associated with alkylator resistance in colon cancer, 14 lymphocytic and myelogenous leukemia, 15,16 gastric cancer, 17 mammary carcinoma, 18,19 prostate cancer, 20 and other malignancies, as reviewed by Raha and Tew. 21 Direct demonstration of the role of GST in drug resistance was achieved by transfecting the GST cDNA (alpha, mu, or pi) into eucaryotic cells.…”