M Ściskalska1, H Milnerowicz. 1. Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland. milena.sciskalska@umed.wroc.pl.
Abstract
OBJECTIVE: The glutathione S-transferases (GSTs) overexpression in hyperproliferating tumour cells resistant to chemotherapy was demonstrated. An increased GST-π activity weakens the efficacy of anti-cancer drugs by promoting their efflux from cells. MATERIALS AND METHODS: This review summarises available information on the physiological role of GSTs, in particular the role of GST-π, in regulation of signalling pathways mechanisms and cellular homeostasis for understanding and explaining the basis for GST-π application as a target for anticancer therapy and implications for clinical practice. RESULTS: GST-π can weaken the effect of TNF receptor-associated factor 2 (TRAF2) on apoptosis signal-regulating kinase-1 by inactivation of MAP kinase pathways (c-Jun N-terminal, p38 kinases). GST-π is involved in the metabolism of endogenous lipids mediators, such as 15-detoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Reduced binding of 15d-PGJ2 to peroxisome proliferator-activated receptors accompanied by GST-π can result in the inhibition of apoptosis. GSTP1 RNA is able to increase the phosphorylation of signal transducer and activator of transcription 3, what results in negative regulation as regards transcriptional activity thereof and affects the growth factor signalling. However, the oxidation of GST-π results in inhibition of TRAF2-GST-π complexes formation and unblocks cell apoptosis. The inhibition of multidrug resistance related proteins 1 (MRP-1) promoter activity and impairment of MRP-1 function can also act as a potent non-competitive inhibitor of GST-π. CONCLUSIONS: GST-π is recognised as an important target in designing new anticancer drugs. These drugs are often substrates for GST-π or have the affinity with its structure, what results in weakening its activity and achieving therapeutic goal.
OBJECTIVE: The glutathione S-transferases (GSTs) overexpression in hyperproliferating tumour cells resistant to chemotherapy was demonstrated. An increased GST-π activity weakens the efficacy of anti-cancer drugs by promoting their efflux from cells. MATERIALS AND METHODS: This review summarises available information on the physiological role of GSTs, in particular the role of GST-π, in regulation of signalling pathways mechanisms and cellular homeostasis for understanding and explaining the basis for GST-π application as a target for anticancer therapy and implications for clinical practice. RESULTS: GST-π can weaken the effect of TNF receptor-associated factor 2 (TRAF2) on apoptosis signal-regulating kinase-1 by inactivation of MAP kinase pathways (c-Jun N-terminal, p38 kinases). GST-π is involved in the metabolism of endogenous lipids mediators, such as 15-detoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Reduced binding of 15d-PGJ2 to peroxisome proliferator-activated receptors accompanied by GST-π can result in the inhibition of apoptosis. GSTP1 RNA is able to increase the phosphorylation of signal transducer and activator of transcription 3, what results in negative regulation as regards transcriptional activity thereof and affects the growth factor signalling. However, the oxidation of GST-π results in inhibition of TRAF2-GST-π complexes formation and unblocks cell apoptosis. The inhibition of multidrug resistance related proteins 1 (MRP-1) promoter activity and impairment of MRP-1 function can also act as a potent non-competitive inhibitor of GST-π. CONCLUSIONS: GST-π is recognised as an important target in designing new anticancer drugs. These drugs are often substrates for GST-π or have the affinity with its structure, what results in weakening its activity and achieving therapeutic goal.