The role of glutathione-S-transferase in anti-cancer drug resistance

• Published in: Oncogene Vol. 22; no. 47; pp. 7369 - 7375
• Main Authors: Townsend, Danyelle M, Tew, Kenneth D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.10.2003; Nature Publishing; Nature Publishing Group
• Subjects: Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antitumor agents; Apoptosis; Asthma; Biological and medical sciences; c-Jun protein; Cancer; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular stress response; Chemotherapy; Detoxification; Drug development; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymes; Etiology; Fundamental and applied biological sciences. Psychology; Glutathione; Glutathione transferase; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; Human Genetics; Humans; Inactivation, Metabolic; Internal Medicine; Isoenzymes; JNK protein; Kinases; Leukotrienes; Ligands; MAP kinase; MAP Kinase Signaling System; Medicine; Medicine & Public Health; Molecular and cellular biology; Multiple sclerosis; Neoplasms - drug therapy; Neoplasms - enzymology; Neurodegenerative diseases; Oncology; Oxidative stress; Prostaglandins; Protein interaction; Proteins; review; Therapeutic targets; Transcription factors; Tumors; MAP kinase pathway; GST; polymorphism; resistance; Resistance; Enzyme; Glutathione transferase; Transferases; Mitogen-activated protein kinase; Malignant tumor; Carcinogenesis; Polymorphism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206940

Glutathione- S -transferases (GSTs) are a family of Phase II detoxification enzymes that catalyse the conjugation of glutathione (GSH) to a wide variety of endogenous and exogenous electrophilic compounds. GSTs are divided into two distinct super-family members: the membrane-bound microsomal and cytosolic family members. Microsomal GSTs are structurally distinct from the cytosolic in that they homo- and heterotrimerize rather than dimerize to form a single active site. Microsomal GSTs play a key role in the endogenous metabolism of leukotrienes and prostaglandins. Human cytosolic GSTs are highly polymorphic and can be divided into six classes: α , μ , ω , π , θ , and ζ . The π and μ classes of GSTs play a regulatory role in the mitogen-activated protein (MAP) kinase pathway that participates in cellular survival and death signals via protein : protein interactions with c-Jun N-terminal kinase 1 (JNK1) and ASK1 (apoptosis signal-regulating kinase). JNK and ASK1 are activated in response to cellular stress. GSTs have been implicated in the development of resistance toward chemotherapy agents. It is plausible that GSTs serve two distinct roles in the development of drug resistance via direct detoxification as well as acting as an inhibitor of the MAP kinase pathway. The link between GSTs and the MAP kinase pathway provides a rationale as to why in many cases the drugs used to select for resistance are neither subject to conjugation with GSH, nor substrates for GSTs. GSTs have emerged as a promising therapeutic target because specific isozymes are overexpressed in a wide variety of tumors and may play a role in the etiology of other diseases, including neurodegenerative diseases, multiple sclerosis, and asthma. Some of the therapeutic strategies so far employed are described in this review.