Induction and Inhibition of Tumor Progression

Warren, Barbour S.; Naylor, Mark F.; Winberg, Lloyd D.; Yoshimi, Naoki; Volpe, John P.; Gimenez-Conti, Irma; Slaga, Thomas J.

doi:10.3181/00379727-202-43511b

Cited by 34 publications

(24 citation statements)

References 16 publications

(19 reference statements)

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“…The expression of GTP has been regarded as a marker of neoplastic progression in several experimental models such as rodent skin and liver chemical carcinogenesis (30). In a clinical study of patients with breast carcinoma, Mishra et al (31) established significantly higher blood levels of GTP in patients with metastasis vs. patients without metastasis and normal controls.…”

Section: Discussionmentioning

confidence: 99%

Glutamine Affects Glutathione Recycling Enzymes in a DMBA-Induced Breast Cancer Model

Kaufmann

Тодорова

Luo

et al. 2008

Nutrition and Cancer

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Malignancy depletes host glutathione (GSH) levels to increase treatment-related toxicity and increases itself to resist the treatments. Our previous studies have shown that dietary glutamine (GLN) prevented 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors through enhancing gut GSH release and reducing tumor GSH level. In addition, GSH synthesis, metabolism, and recycling are accomplished in gamma-glutamyl cycle. We hypothesized that the GLN prevention might be through a differential regulation of the gamma-glutamyl cycle enzymes. Female Sprague-Dawley rats were randomized into DMBA-tumor bearing, DMBA-treated, and control groups subdivided into GLN and water groups. GLN supplementation was given at 1 g/kg/day by gastric gavage. The activities and messenger RNA levels of gamma-glutamyl transpeptidase (GTP), gamma-glutamylcysteine synthetase (GCS), 5-oxo-L-prolinase (OPase), gamma-glutamyl transferase (GTF), and glutaminase (GLNase) were determined in gut mucosa and breast tumor using specific enzyme assays and semiquantitative reverse transcription polymerase chain reaction. GLN upregulated gut GTP, GCS, OPase, and GLNase in DMBA-tumor bearing, DMBA-treated, and/or control rats; however, it downregulated these enzymes in the tumor. The paradoxical effect of GLN on key GSH recycling enzymes in the gut versus tumor suggests that dietary supplemental GLN could be used in the clinical practice to increase the therapeutic index of cancer treatments by protecting normal tissues from, and sensitizing tumor cells to, chemotherapy and radiation-related injury.

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Section: Discussionmentioning

confidence: 99%

Glutamine Affects Glutathione Recycling Enzymes in a DMBA-Induced Breast Cancer Model

Kaufmann

Тодорова

Luo

et al. 2008

Nutrition and Cancer

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“…In addition, the overexpression of GGT led to a reduction in cellular glutathione levels. 23 These results suggest that high levels of cellular glutathione prevent tumor progression and low cellular glutathione levels favor tumor progression. teine and some derivatives, and N-acyldehydroaniline derivatives have been shown to inhibit tumor progression.…”

Section: Inhibition Of Tumor Progression By Antioxidantsmentioning

confidence: 95%

“…When injected subcutaneously, all the GGT transfected clones formed malignant tumors, while only 24% of the vector control transfected cells produced tumors. 23 The GGT-transfected grafts had an average mass that was almost three times that of the vector control transfected cells. In addition, the overexpression of GGT led to a reduction in cellular glutathione levels.…”

Section: Inhibition Of Tumor Progression By Antioxidantsmentioning

confidence: 99%

“…Glutathione, ethyl ester of glutathione, and 7V-acetylcysteine were found to inhibit skin tumor progression. 23 Although BHA and vitamin C at high doses inhibited skin tumor progression, they were not very effective. Recently, low doses of N-acyldehydroaniline derivatives were found to be very effective in counteracting skin tumor progression.…”

Section: Inhibition Of Tumor Progression By Antioxidantsmentioning

confidence: 99%

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Inhibition of skin tumor initiation, promotion, and progression by antioxidants and related compounds

Slaga

1995

Critical Reviews in Food Science and Nutrition

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Antioxidants have been shown to inhibit the induction of cancer by a wide variety of chemical carcinogens and radiation at many target sites in mice, rats, hamsters, and man. Evidence is accumulating that suggests that free radicals are important in all stages of chemical carcinogenesis. Both carcinogens and tumor promoters have also been shown to decrease the cellular activity of superoxide dismutase and catalase. A number of antioxidants and related compounds were tested to determine if they would inhibit either skin tumor initiation, promotion, or progression. In terms of skin tumor initiation, compounds such as BHT, vitamins E and C, and CuDIPS have been found to inhibit DMBA skin tumor initiation. The mechanism of action of these compounds appears to be related to their effect on the metabolism of DMBA, as BHT and CuDIPS do not inhibit the initiating activity of BP-diol-epoxide and MNNG. Although several antioxidants do inhibit skin tumor initiation by procarcinogens, antioxidants are in general much more effective inhibitors of skin tumor promotion. BHT, BHA, parahydroxyanisole, disulfiran, and vitamins E and C as well as many other antioxidants are very effective inhibitors of skin tumor promotion. We also determined the effect of free radical scavengers on the progression process. Of the agents tested, glutathione and N-acyl dehydroalamines were the most effective in reducing carcinoma incidence. Diethyl maleate, a chemical that reduces glutathione levels, was effective in enhancing progression. In addition, overexpression of gamma-glutamyltranspeptidase (GGT), which leads to a reduction in cellular glutathione levels, also enhances progression.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The overexpression of keratin 13 is thought to be a good marker for skin tumor progression (Warren et al, 1993;Slaga et al, 1995). The expression of keratin 13 was much higher in ULTH cells than in control cells ( Figure 3a and b).…”

Section: Ulth Cells Exhibit Increased Keratin 13 Expressionmentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVAlong-treated (24 J/cm 2 once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC r -nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.

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Induction and Inhibition of Tumor Progression

Cited by 34 publications

References 16 publications

Glutamine Affects Glutathione Recycling Enzymes in a DMBA-Induced Breast Cancer Model

Glutamine Affects Glutathione Recycling Enzymes in a DMBA-Induced Breast Cancer Model

Inhibition of skin tumor initiation, promotion, and progression by antioxidants and related compounds

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

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