Implications of Glutathione-S-transferases in Mitogen-activated protein kinase pathway: Risk associated with anticancer drug resistance

Abstract

Anticancer drug resistance is a perilous glitch to accomplish alleviation of disease in patients with cancer. The setback of drug resistance in chemotherapy is a weighty snag of present time. Hassle of carcinoma has ability to develop resistance that arises due to certain alterations in drug targets. In the course of anticancer administrations, development of targeted therapies anticipates a new arena to subdue the drug resistance. Exalted levels of certain glutathione transferase isozymes have been identified with malign transformations as well as with anticancer drug resistance. Glutathione-S-transferases are a large group of phase-II detoxification enzymes which catalyse the conjugation of reduced glutathione to a broad range of exogenous as well as endogenous compounds. The enzymes of this family are divided into two distinct subgroups namely: cytosolic enzymes and membrane bound microsomal enzymes. Human cytosolic glutathione-S-transferases are extremely polymorphic in nature and exist in many forms such as mu, pi, alpha, theta, omega and zeta. Among these enzymes, mu and pi classes take part in regulation of mitogen-activated protein kinase pathway in directing cellular responses with apoptosis signal-regulating kinase and c-Jun Nterminal kinase 1 protein interactions. In normal condition, these two protein are mainly activated in response to cellular stress. The implications of glutathione S-transferase in development of anticancer drug resistance have been observed in two distinct ways. The first way is through direct detoxification mechanism while the second way deals with the action of glutathione S-transferase (mu and pi forms) as inhibitor to mitogen-activated protein kinase pathway.