Effect of dietary glutamine on tumor glutathione levels and apoptosis-related proteins in DMBA-induced breast cancer of rats

Abstract

Glutamine (GLN) is a non-essential amino acid that is present in nearly every biochemical pathway and is the major intraorgan nitrogen carrier. GLN via glutamate, is one of the precursors for the synthesis of glutathione (GSH), the major endogenous antioxidant in mammalian cells, which protects them from oxidative injury and cell death. Cancer cells have higher GSH levels than the surrounding normal cells, which attributes to a higher rate of cell proliferation and resistance to chemotherapy. Therefore, selective tumor depletion of GSH presents a promising strategy in cancer treatment. Experimental studies have associated decreased GSH levels with inhibition of proliferation and stimulation of apoptosis. Previous results of our laboratory have provided evidence that dietary GLN diminished tumor development in implantable as well as 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer and elevated GSH in the host tissues. In this study we examined the effects of GLN on GSH levels in DMBA-induced mammary tumors and correlated the results with protein and mRNA expression of apoptosis-related proteins Bcl-2, Bax and caspase-3 in tumor cells. The results have shown that GLN supplementation caused a significant decrease in the tumor GSH levels and the ratio GSH/oxidized GSH (GSSG), accompanied by up-regulation of Bax and caspase-3, and down-regulation of Bcl-2. These findings suggest that dietary GLN supplementation suppresses mammary carcinogenesis by activation of apoptosis in tumor cells and this probably is a result of GSH down-regulation.

Antioxidant Treatments: Effect on Behaviour, Histopathological and Oxidative Stress in Epilepsy Model

“…During 1 h of acute phase of seizures, no case of fatality was observed between the adult rats. However, during the 24 h observation of this phase, 63% of adult animals died (Cavalheiro et al, 1994;Todorova et al, 2004). Similarly, these results for the behavioral alterations in pilocarpine model were described previously by Marinho et al (1998).…”

The Stance of Antioxidants in Brain Tumors

“…The most important H 2 O 2 scavenging enzymes and concerned proteins having antioxidant capacity comprise CAT, GPx, GR enzymes associated with the synthesis of reduced GSH (Halliwell & Gutteridge, 1996) and a group of cysteine containing proteins known as thioredoxins, thioredoxin peroxidases (peroxiredoxins), and glutaredoxins (Kumar & Holmgren, 1999;Rhee, et al, 1999;Powis, et al, 2000;Holmgren, 2000). When ROS production is enhanced, the antioxidant scavenging capacity is disturbed and this results in the development of oxidative stress which leads to tissue injury and apoptosis activation (Todorova, et al, 2004).…”

Increased chemosensitivity and elevated reactive oxygen species are mediated by glutathione reduction in glutamine deprived neuroblastoma cells

“…In breast cancers of rats, it was suggested that dietary glutamine supplementation decreased tumor GSH levels and suppressed cells by activation of apoptosis in tumor cells (Todorova et al 2004). Studies on Ehrlich ascites tumors (Carretero et al 2000) and melanomas (Benlloch et al 2006) demonstrated that a glutamine enriched diet increases glutaminase activity, promotes accumulation of cytosolic glutamate and inhibits GSH transport into mitochondria.…”