The Discovery and Application of Inhibitors of Glutathione S-Transferase as Therapeutic Agents -A Review

Abstract

Glutathione S-transferases (GSTs) are phase II detoxification enzymes that function in the conjugation of glutathione (GSH) to cytotoxic substances rendering them water soluble and easily excreted from the body. Many tumor cells tend to strongly increase the expression of GST, and this is thought to be associated with a poor prognosis for response to anticancer treatment of patients. Such in vitro over-expression of GST may indeed be the basis of the reduced sensitivity of cancer cells to cytostatics. Alkylating anticancer drugs have been found to be effectively conjugated to GSH, catalyzed by GST, thereby decreasing the potency of such drugs. GSTs are also believed to detoxify endogenous substances that are formed as a consequence of oxidative stress, protecting cancer cells against cytostatic-induced oxidative stress and, subsequently, apoptosis. In addition, GSTs inhibit the mitogen-activated protein kinase signal transduction pathway by binding proteins that play major roles in transmission of cellular survival and death signals. These result in a reduced activity of apoptosis-dependent anticancer drugs due to high GST activity in cancer cells. GST has also been proposed to be the major detoxification tool that protects parasites against the host immune response and antiparasitic drugs. In order to ameliorate these resistances, a rationale has been established to utilize agents that specifically inhibit the various classes of GST as adjuvant in chemotherapy. In the past two decades, several compounds have been reported to selectively inhibit GST isoenzymes. In this review, synthetic and naturally occurring organic compounds exhibiting GST inhibition will be described. Keywords: Glutathione S-transferase, glutathione S-transferase inhibitors, therapeutic agents, cancer chemotherapy, natural products, apoptosis, drug resistance