Abstract 3229: Energy restriction caused by the glycolytic inhibitor, 2-Deoxy-D-Glucose inhibits chemical induced carcinogenesis in mice

Abstract

Abstract Enhanced glucose metabolism is a fundamental metabolic change in most of the tumors which drives the process of tumorigenesis. Dietary Energy Restriction (DER) is a promising approach to target this enhanced glycolysis for combating cancer but is difficult to sustain. Therefore, metabolic modifiers like 2-Deoxy-D-Glucose (2-DG) has been used as Energy Restriction Mimetic (ERM) without causing under-nutrition. In the present studies we have investigated the effects of 2-DG on the two-stage model of 7, 12-dimethylbenz (a) anthracene-tumor promoting agent (DMBA-TPA) induced skin tumours (papillomagenesis) in mice. TPA containing phorbol ester promotes tumorigenesis by generating reactive oxygen species, increasing epidermal DNA synthesis and cellular proliferation along with the mutation caused by DMBA. On the other hand, Energy Restriction (ER) modulates oxidative stress and enhances activities of superoxide dismutase, catalase, and glutathione peroxidase in the livers of rats. Therefore, studies were designed to examine the effects of 2-DG administered at the initiation or at the promotion phase of papillomagenesis along with the modulation of the antioxidant defense system upon chronic energy restriction created by 2-DG. 2-DG administration (0.2% & 0.4% w/v) in daily drinking water was started pre- or post-TPA application to the DMBA initiated skin of Swiss Albino mice (male, n=4/group) till the termination of the study. Tumor incidence, latency, tumour burden and yield were observed. Lipid peroxidation, GSH level, SOD and catalase activities were analyzed in the liver. Chronic administration of 2-DG did not significantly alter body weight, serum lactate and blood glucose levels suggesting maintenance of general health and physiological status. A significant reduction in tumor incidence with increased tumor latency was observed, which was 2-DG dose dependent; 50 % with pre-TPA and 25% post-TPA in 0.2% 2-DG group; and 0 % with post-TPA in 0.4%2-DG group with average number of tumors per tumor bearing mouse being 1, 1, and 0 respectively. Interestingly, tumor incidence in the 0.4% 2-DG group (pre-TPA) was 100%, with average number of tumors 2.5 per animal. Under these conditions, 2-DG significantly enhanced the level of reduced glutathione (GSH) with a concomitant reduction in the lipid peroxidation, with no changes observed in SOD and catalase activities in the liver. These observations suggest that the protective potential against skin carcinogenesis is partly linked to the augmentation of anti-oxidant defence system. Taken together, the present studies demonstrate that dietary 2-DG can inhibit papillomagenesis. Although, the exact mechanisms underlying cancer preventive potential of 2-DG is not completely understood, it appears to be partly due to the upregulation of the non-enzymatic antioxidant defence system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3229. doi:1538-7445.AM2012-3229