Effects of glutathione depletion on the cytotoxicity of agents toward a human colonic tumour cell line

Abstract

Summary Levels of glutathione (GSH) in tumour tissue may be important in determining the clinical response to certain anticancer agents. Recent reports have suggested that D,L-buthionine-S,R-sulphoximine (BSO), a specific inhibitor of GSH synthesis, may be used to deplete tumour cell GSH and thus increase the therapeutic ratio of these agents. We have previously shown that 1-naphthol is a potential antitumour agent, and that its possible metabolite 1,4-naphthoquinone is thiol reactive and capable of redox cycling. It was therefore of interest to investigate the effect of pretreatment with BSO, on the toxicity of these agents, to tumour cells. For comparison we included three other cytotoxic agents, melphalan, helenalin and menadione, the toxicities of which are reported to be modulated by intracellular GSH. Depletion of GSH using BSO did not effect the toxicity of 1-naphthol, or 1,4-NQ but did produce slight potentiation of the cytotoxicities of menadione, helanalin and melphalan. The lack of effect of BSO on 1-naphthol and 1,4-NQ is not easily explained but if one also considers the modest potentiation of cytotoxicity achieved with the other agents studied, the potential use of BSO in combined chemotherapy is at best rather modest.Based on our findings that l-naphthol is selectively toxic to short term organ cultures of human colonic tumour tissue compared to normal colonic tissue from the same patients, we suggested the potential use of l-naphthol or related compounds in cancer chemotherapy (Cohen et al., 1983;Wilson et al., 1985). Recently we have also shown an antitumour activity of l-naphthol against Ehrlich ascites tumour cells (Jones et al., 1987) and it therefore is of interest to elucidate its mechanism of toxicity and formation of possible reactive metabolites. l-Naphthol may be metabolised by a microsomal mixed function oxidase to cytotoxic naphthoquinones, primarily 1,4-naphthoquinone (d'Arcy Doherty et al., 1984a, b, 1985). The toxicity of both 1-naphthol and its possible metabolites 1,2-naphthoquinone and 1,4-naphthoquinone, to isolated hepatocytes, is prececed by a rapid depletion of intracellular glutathione (GSH) (d 'Arcy Doherty et al., 1984b).GSH is the major nonprotein thiol in the cell and plays a critical role in cellular defences against oxidative stress, free radicals and alkylating agents (Meister & Anderson, 1979). One of the problems associated with chemotherapy is the wide range of sensitivities to treatment with any or one agent, which is thought to be, in part, due to the differences in sulphydryl levels in tumours. Several recent reports, have therefore considered the potential of modulating intracellular GSH levels in order to increase the chemotherapeutic efficacy of certain antitumour agents, whose toxicity is modulated by GSH (Akman et al., 1985;Arrick et al., 1983;Capranico et al., 1986;Hamilton et al., 1985;Russo et al., 1986;Suzukake et al., 1982Suzukake et al., , 1983.The cytotoxic and antitumour effects of certain quinones e.g. adriamycin and menadione, are thought to be r...

Thiol-mediated apoptosis in prostate carcinoma cells

“…40 BSO, however, has been shown to be unable to enhance significantly the potentiation of cytotoxicity of melphalan and other chemotherapeutic agents, including menadione and helanlin, in other tumor cell lines. 41 GSH-based approaches to improving treat- ment for a number of other cancers have also been reviewed. [42][43][44] Chemical depletion of GSH by DEM in combination with the administration of ATP and Xrays has been shown to lead to complete regression of 95% Ehrlich tumors in mice.…”

Chrysin enhances doxorubicin-induced cytotoxicity in human lung epithelial cancer cell lines: The role of glutathione

“…The efficacies of radiation and many chemotherapeutics are partly due to and enhanced by increased oxidative stress in cancer cells (Mallery et al , 1999; Kovacic and Osuna, 2000; Kovacic, 2007; Marelli et al , 2008). Altering GSH metabolism and turnover is one way to increase oxidative stress (Jordan et al , 1987; Calvert et al , 1998; Schnelldorfer et al , 2000; Estrela et al , 2006; Mena et al , 2007). For example, carmustine (BCNU) is an alkylating agent currently used in treatment for many cancers including lung, colon, multiple myeloma, and brain tumors.…”

Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells

“…In addition inconsistent results have been reported regarding BSO's effect on the chemosensitivity of a single cell line treated with a variety of drugs as well as it's effect on different tumor types treated with a single agent ]reviewed in 25]. In this and in previous studies, insufficient GSH depletion is unlikely to have been the causative factor [25][26][27]. In order to standardize our chemosensitivity screening procedure, a fixed dose of BSO was used for all samples.…”

“…The reasons why BSO failed to produce chemosensitization in all tumors remain to be defined. However, other investigators have reported a similar lack of enhanced tumor cell kill following BSO [25][26][27]. In addition inconsistent results have been reported regarding BSO's effect on the chemosensitivity of a single cell line treated with a variety of drugs as well as it's effect on different tumor types treated with a single agent ]reviewed in 25].…”