Glutamine supplementation reduces glutathione levels and stimulates apoptosis in DMBA-induced mammary tumors

Todorova, Valentia; Kaufmann, Yihong; Luo, Shaoke; Harms, Stacy A.; Babb, Kirk; Klimberg, V. Suzanne

doi:10.1016/j.jss.2003.08.019

Cited by 6 publications

(11 citation statements)

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“…Our previous studies showed that dietary Gln maintained normal cardiac GSH levels in rats given DOX and prevented cardiac lipid peroxidation (18). We have also found that Gln did not affect tumor GSH (19). This is important, because GSH is a key regulator of the cellular redox state and the redox environment within the tumor cells determines the response of tumors (and protection of the normal cells) to chemotherapy and radiation (20).…”

Section: Introductionmentioning

confidence: 94%

Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

Тодорова

Kaufmann

Hennings

et al. 2010

The Journal of Nutrition

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Doxorubicin (DOX), a widely used anticancer drug, has a dose-dependent cardiotoxicity, attributed mainly to free radical formation. The cardiomyocyte oxidative stress occurs rapidly after DOX treatment, resulting in harmful modifications to proteins, lipids, and DNA. Previous data showed that oral l-glutamine (Gln) prevented cardiac lipid peroxidation and maintained normal cardiac glutathione (GSH) levels in DOX-treated rats. Our aim in this study was to examine the effect of Gln on DOX-induced cardiac oxidative stress in a tumor-bearing host. Female Fisher344 rats with implanted MatBIII mammary tumors were randomized into 2 groups: a Gln group that received l-Gln (1 g.kg(-1).d(-1)) (n = 10) via a Gln-enriched diet and/or gavage with 50% Gln suspension during the whole experiment and a control group that was fed the same diet formulation without Gln and/or were gavaged with water. All rats received a single injection of 12 mg/kg DOX and were killed 3 d later. GSH levels of hearts, livers, tumors, and blood, as well as cardiac histological alterations, lipid peroxidation, peroxinitrite levels, and caspase-3 activation were determined. Cardiac physiologic alterations were assessed by ultrasound imaging before and 3 d after DOX administration. The Gln supplementation resulted in lower cardiac lipid peroxidation and peroxintrite levels and elevated cardiac catalase enzyme activity and GSH compared with the controls, without affecting those of the tumors. DOX-induced alterations of the echocardiographic parameters were significantly reduced in the Gln-supplemented rats. These data indicate that Gln is able to reduce the oxidative damage of cardiomyocytes that occurs soon after DOX administration and thus protects the heart of a tumor-bearing host from DOX-induced cardiomyopathy.

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Section: Introductionmentioning

confidence: 94%

Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

Тодорова

Kaufmann

Hennings

et al. 2010

The Journal of Nutrition

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“…[23][24][25] Literature lucid with evidence showed that L-glutamine (LG) possesses potent antiulcer, antioxidant, anti-bacterial, cardioprotective, anticancer, hepatoprotective, and anti-apoptotic potential. [26][27][28][29] It has been reported that LG significantly attenuated cisplatin-induced genotoxicity. 30 However, its role in DN is yet to unravel.…”

Section: Introductionmentioning

confidence: 99%

Protective effect ofL-glutamine against diabetes-induced nephropathy in experimental animal: Role of KIM-1, NGAL, TGF-β1, and collagen-1

Sadar¹,

Kaspate

Vyawahare³

2016

Renal Failure

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Diabetic nephropathy is a serious microvascular complication and one of the main causes of endstage renal disease. L-Glutamine (LG) is naturally occurring amino acids with antidiabetic and antioxidant potential. The aim of present investigation was to evaluate the potential of LG against streptozotocin (STZ)-induced diabetic nephropathy (DN) in laboratory rats. DN was induced in male Wistar rats (200-220 g) by intraperitoneal administration of STZ (55 mg/kg). Animals were treated orally with either distilled water (10 mg/kg) or LG (250, 500, and 1000 mg/kg) or Sitagliptin (5 mg/kg). Various biochemical, molecular, and histological (hematoxylin-eosin and Masson's trichrome stain) parameters were assessed. Administration of LG (500 and 1000 mg/kg) significantly inhibited (p < .05) STZ-induced alterations in serum and urine biochemistry (urine creatinine, uric acid, albumin, and BUN). It also significantly increased creatinine clearance rate. STZ induced increase in renal oxidonitrosative stress was significantly decreased (p < .05) by LG (500 and 1000 mg/kg) treatment. Upregulated renal KIM-1, NGAL, TGF-b1, and collagen-1 mRNA expression after STZ administration was significantly inhibited (p < .05) by LG (500 and 1000 mg/ kg) treatment. Correlation analysis also revealed that antidiabetic potential of LG attenuates STZinduced elevated renal KIM-1, NGAL, TGF-b1, and collagen-1 mRNA expression. Histopathological alteration induced by STZ in renal tissue was ameliorated by LG treatment. In conclusion, results of present investigation suggest that treatment with LG ameliorated STZ-induced DN via the inhibition of oxidonitrosative stress as well as downregulation of KIM-1, NGAL, TGF-b1, and collagen-1 mRNA expressions. ARTICLE HISTORY

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“…The results published elsewhere (22,31,34), showed that tumor development was significantly (P = 0.007, GLN vs. control, Fisher Exact Test) reduced by GLN supplementation at the end of the study (11 wk after DMBA application). The GLN-supplemented group had 50% less tumors in comparison with the control group (Fig.…”

Section: Effect Of Dietary Gln On Carcinogenicity Of Dmbamentioning

confidence: 74%

“…Total protein extracts were prepared from 1) eight randomly selected tumors of each GLN-supplemented-and control groups and 2) non-tumorous mammary tissue of 8 rats from the control group and 16 rats from the GLN-supplemented group, including 8 rats with tumors and 8 rats without tumors, as described previously (22). All tumors and normal mammary tissue were evaluated independently.…”

Section: Protein Extracts and Western Blotingmentioning

confidence: 99%

“…There is no direct evidence that GLN availability affects cellular redox state (1), however several reports suggest that supplementation with GSH constituent amino acids inhibit tumor promotion, at least in part, by their interference with the GSH metabolism (19,20). Our previous studies found that dietary GLN caused a significant decrease in tumor GSH levels with a resulting reduction in GSH/GSSG (21,22) in 7,12-dimethylbenz(a)anthracene (DMBA)-breast cancer model. In the normal, non-tumorous mammary tissues, serum and gut mucosa, however, GLN caused a several-fold increase in GSH content (23).…”

Section: Introductionmentioning

confidence: 99%

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Modulation of p53 and c-myc in DMBA-Induced Mammary Tumors by Oral Glutamine

Тодорова

Kaufmann²,

Luo

et al. 2006

Nutrition and Cancer

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Previous studies established that oral glutamine (GLN) reduced tumor development in implantable and 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer models. This finding was associated with a decrease in tumor glutathione (GSH) levels, while maintaining normal gut, blood, and breast GSH. Alterations in GSH levels contribute to the control of apoptotic and cell cycle-regulating signaling. The aim of this study was to examine the role of dietary GLN on activation of p53 and c-myc, which play critical roles in cancer development and sensitivity to radiation and chemotherapy. Mammary gland carcinomas were induced in rats by DMBA. The rats were gavaged daily with GLN or water (controls), starting 1 wk prior DMBA-application and throughout the duration of the experiment (11 wk after DMBA). Tumor DNA was examined for mutations in p53 exons 5 and 6. Protein and mRNA levels of p53, p21(WAF1/CIP1), PTEN, IGF-IR, mdm2, and c-myc in tumors of GLN-supplemented rats were compared with those of the control rats (received water). The sequencing of p53 showed that it was wild type. Increased phosphorylation of p53, as well as higher mRNA and protein levels of p21(WAF1/CIP1), PTEN, and mdm2, and lower levels of IGF-IR were detected in tumors of GLN-supplemented rats vs. controls. Both phosphorylated c-myc and c-myc mRNA levels were reduced by GLN. The up-regulation of tumor p53 signaling and down-regulation of c-myc, in addition to previously established inhibition of Akt signaling in DMBA-breast cancer model, suggest that dietary GLN could be a useful approach for increasing the effectiveness of cancer treatment.

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Glutamine supplementation reduces glutathione levels and stimulates apoptosis in DMBA-induced mammary tumors

Cited by 6 publications

References 0 publications

Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

Oral Glutamine Protects against Acute Doxorubicin-Induced Cardiotoxicity of Tumor-Bearing Rats

Protective effect ofL-glutamine against diabetes-induced nephropathy in experimental animal: Role of KIM-1, NGAL, TGF-β1, and collagen-1

Modulation of p53 and c-myc in DMBA-Induced Mammary Tumors by Oral Glutamine

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