Potential for selective modulation of glutathione in cancer chemotherapy1
Introduction
The concept of selective glutathione (GSH) modulation cited in this report refers to the strategy of the preferential modulation of GSH in normal or tumor cells. The feasibility of such selectivity depends on the physiological difference between normal and tumor cells, which upon exposure to a selective GSH modulator, leads to the different responses in the two types of cells. In this chapter the authors report the preliminary studies of three targets under the investigation for selective GSH modulation: γ-glutamylcysteine synthetase (γ-GCS), 5-oxo-l-prolinase (5-OPase) and gap junction intercellular communication (GJIC).
Section snippets
GSH modulation
GSH (l-glutamyl-l-cysteinyl-glycine) is a tripeptide thiol found in virtually all cells. Biosynthesis and metabolism of GSH is carried out via the function of the γ-glutamyl cycle which is composed of a series of inter-related enzymatic reactions [1](Fig. 1). The de novo synthesis pathway of GSH includes two sequential, ATP-dependent enzymatic steps from the constituent amino acids glutamate (GLU), cysteine and glycine via the function of γ-GCS, the rate limiting step which forms an amide
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Biochemical and mitochondrial membrane potential changes relating to betulinic acid-mediated anticancer activity in murine ascites Dalton's lymphoma
2022, Phytomedicine PlusCitation Excerpt :Depletion of GSH levels could increase the cytotoxicity of a variety of anticancer agents (Khynriamand Prasad, 2003). GSH depletion can be seen to enhance the antitumor cytotoxicity of various drugs without increasing toxicity to normal tissue (Chen et al., 1998). The observed time-dependent decrease in GSH level in DL cells after BA treatment (Fig. 2A) is an important step in its antitumor activity as it may lead to a decrease in the antioxidant potential and protective ability of these cells thereby, increasing the host's survivability.
Role of connexin 32 in acetaminophen toxicity in a knockout mice model
2014, Experimental and Toxicologic PathologyCitation Excerpt :Hepatic GSH was reported to be a rate-determining protein for detoxification of APAP hepatotoxicity (Bajt et al., 2003). GSH is abundantly contained in the periportal zone of the hepatic lobules, and spreads from cell to cell via GJIC (Frankfurt et al., 1991; Barhoumi et al., 1993; Chen et al., 1998). In our study, reductions in hepatic GSH and GSSG contents and decreases in GSH staining in Cx32KO mice were relatively mild compared to those in wild-type mice.
Glutathione and glutathione analogues; Therapeutic potentials
2013, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Enhancing the capacity of GSH, and its associated enzymes, to protect cells from redox-related perturbations or environmental toxins represents a longtime and persistent aim for those searching for cytoprotective approaches to prevention of cancer, neurologic degeneration, pulmonary and inflammatory conditions, as well as cardiovascular ailments [1–3]. Efforts to increase cellular GSH levels by the direct administration of reduced glutathione face limitations by solubility, absorption and stability [4]. This has resulted in a significant effort to identify GSH analogues or precursors, or to generate mimic molecules with the capacity to reduce oxygen radical and peroxidation related effects on cells.
Utilization of 6-(methylsulfinyl)hexyl isothiocyanate for sensitization of tumor cells to antitumor agents in combination therapies
2013, Biochemical PharmacologyCitation Excerpt :The results of our in silico analyses were confirmed by in vitro experimental evidence, and the present study reveals that 6-MITC in combination strategies could be used for depleting GSH and sensitizing tumor cells to antitumor agents, leading to their eradication. GCL and its product GSH have been associated with various cancers and identified as possible targets for the prevention and therapy of cancer [33–45]. Molecular modeling has gained great importance in drug discovery and development [78–80], and further in silico analyses of GCL and its interactions with possible ligands are anticipated.
Expression of glutathione S-transferase π and glutathione synthase correlates with survival in early stage non-small cell carcinomas of the lung
2007, Human PathologyCitation Excerpt :In other neoplasms, these proteins have been implicated in inhibition of tumor cell apoptosis and chemotherapy resistance. Indeed, studies investigating chemotherapeutic agents, which primarily act on the glutathione pathway, are currently in progress [39,40]. One GST-π–activated prodrug, TLK-286, is currently under phase III testing in NSCLC patients [41].
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Presented at the International Conference on Glutathione and Glutathione-Linked Enzymes in Human Cancer and Other Diseases, Hilton Head, SC, USA, November 1996.