Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model

Abstract

Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.

Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4‐NQO‐induced carcinogenesis

“…The induction of GSH-related detoxification is thought to be a primary mechanism by which numerous antioxidant-based chemopreventive agents work, 60 including selenium, 61 N-acetylcysteine 62,63 and 2-oxothiazolidine-4-carboxylic acid 64 and thiol-related compounds found in garlic such as S-allylcysteine. 65 Additionally, topical application of GSH inhibited tumor progression in the murine skin multistage carcinogenesis model 66 and dietary GSH produced a significant regression of aflatoxin B1-induced hepatocellular carcinoma in rats. 67 The mechanisms by which GSH levels are upregulated during carcinogenesis are unknown.…”

The effectiveness of a mixture of β‐carotene, α‐tocopherol, glutathione, and ascorbic acid for cancer prevention

“…The cancer prevention activity of glutathione has also been demonstrated in experimental models (8,9). The anticancer activity of ascorbic acid has not been definitively demonstrated, but its importance in metabolism is well defined, and one of its actions is to stabilize the action of tocopherol (10).…”

Induction and Inhibition of Tumor Progression

“…To evaluate the role of oxidative damage in tumor progression, we designed studies to both increase (discussed later) and decrease the levels of GSH in papilloma-bearing skin. Diethyl maleate has been demonstrated to decrease the GSH content of mouse skin after topical treatment (20). Biweekly topical treatment of papilloma-bearing skin with 30 pmol of diethylmaleate led to a 1.6-fold increase in the percentage of mice that developed carcinomas (Fig.…”