Glutathione S-transferases as regulators of kinase pathways and anticancer drug targets.
Anticancer drug development using the platform of glutathione (GSH), glutathione S-transferases (GST) and pathways that maintain thiol homeostasis has recently produced a number of lead compounds. GSTpi is a prevalent protein in many solid tumors and is overexpressed in cancers resistant to drugs. It has proved to be a viable target for pro-drug activation with at least one candidate in late-stage clinical development. In addition, GSTpi possesses noncatalytic ligand-binding properties important in the direct regulation of kinase pathways. This has led to the development and testing of agents that bind to GSTpi and interfere with protein-protein interactions, with the phase II clinical testing of one such drug. Attachment of glutathione to acceptor cysteine residues (glutathionylation) is a posttranslational modification that can alter the structure and function of proteins. Two agents in preclinical development (PABA/NO, releasing nitric oxide on GST activation, and NOV-002, a pharmacologically stabilized pharmaceutical form of GSSG) can lead to glutathionylation of a number of cellular proteins. The biological significance of these modifications is linked with the mechanism of action of these drugs. In the short term, glutathione-based systems should continue to provide viable targets and a platform for the development of novel cancer drugs.
Townsend
Danyelle M
DM
Medical University of South Carolina, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Charleston, South Carolina, USA.
Findlay
Victoria L
VL
Tew
Kenneth D
KD
D010129:4-Aminobenzoic Acid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism; D003603:Cytotoxins / Q000737:chemistry / Q000378:metabolism; D004338:Drug Combinations; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D019803:Glutathione Disulfide / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress; D011355:Prodrugs; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D062366:para-Aminobenzoates
D000970:Antineoplastic Agents; D001391:Azo Compounds; D003603:Cytotoxins; D004338:Drug Combinations; C529375:NOV 002; C485370:O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate; D011355:Prodrugs; D062366:para-Aminobenzoates; C107479:TER 286; D005982:Glutathione Transferase; D011494:Protein Kinases; D005978:Glutathione; D002945:Cisplatin; D010129:4-Aminobenzoic Acid; D019803:Glutathione Disulfide