Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells

Monaco, Marco Di; Pizzini, A; Gatto, V; Leonardi, Luiz Sérgio; Gallo, Marco; Brignardello, Enrico; Boccuzzi, Giuseppe

doi:10.1038/bjc.1997.102

Cited by 58 publications

(40 citation statements)

References 24 publications

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“…The decrease in NADPH generation due to G6PD inhibition might impair aldose reductase activity, thus reducing the accumulation of sorbitol within BRP. However, this mechanism is unlikely, since the well known inhibitory effect of DHEA on G6PD is observed only at concentrations much higher than those used in this study (Boccuzzi et al 1993, Butler et al 1993, Di Monaco et al 1997.…”

Section: Discussionmentioning

confidence: 68%

Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity

Brignardello¹,

Beltramo²,

Molinatti³

et al. 1998

Journal of Endocrinology

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Pericyte loss is an early feature of diabetic retinopathy and represents a key step in the progression of this disease. This study aimed to evaluate the effect of dehydroepiandrosterone (DHEA) on glucose toxicity in retinal capillary pericytes. Bovine retinal pericytes (BRP) were cultured in a high glucose concentration, with or without DHEA. After 4 days of incubation the number of BRP was significantly reduced by the high glucose concentration. The addition of DHEA to the medium reversed the adverse effect of high glucose: BRP proliferation partially recovered in the presence of 10 nmol/l DHEA, and completely recovered in the presence of DHEA at concentrations equal to or greater than 100 nmol/l. At physiological glucose concentrations, DHEA had no effect on BRP growth. Data show that DHEA, at concentrations similar to those found in human plasma, protects BRP against glucose toxicity. This effect seems specific for DHEA, since its metabolites, 5-en-androstene-3 ,17 -diol, dihydrotestosterone and estradiol did not alter BRP growth in normal or high glucose media. Various pieces of evidence link the antioxidant properties of DHEA to its protective effect on glucose-induced toxicity in BRP.

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Section: Discussionmentioning

confidence: 68%

Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity

Brignardello¹,

Beltramo²,

Molinatti³

et al. 1998

Journal of Endocrinology

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“…Other studies in cancer have failed to show any effects of DHEA on G6PDH. 37,38 We believe that our proposed mechanism is independent of these potential DHEA effects. First, in our human VSMCs, the DHEA-induced inhibition of Akt was prevented in the presence of GPCR inhibitors and mimicked by cell-impermeable BSA-DHEA, suggesting complete dependence on membrane signaling, not cytosolic action.…”

Section: Discussionmentioning

confidence: 98%

Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-β/NFAT Axis

et al. 2009

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Background-The remodeled vessel wall in many vascular diseases such as restenosis after injury is characterized by proliferative and apoptosis-resistant vascular smooth muscle cells. There is evidence that proproliferative and antiapoptotic states are characterized by a metabolic (glycolytic phenotype and hyperpolarized mitochondria) and electric (downregulation and inhibition of plasmalemmal K ϩ channels) remodeling that involves activation of the Akt pathway. Dehydroepiandrosterone (DHEA) is a naturally occurring and clinically used steroid known to inhibit the Akt axis in cancer. We hypothesized that DHEA will prevent and reverse the remodeling that follows vascular injury. Methods and Results-We used cultured human carotid vascular smooth muscle cell and saphenous vein grafts in tissue culture, stimulated by platelet-derived growth factor to induce proliferation in vitro and the rat carotid injury model in vivo. DHEA decreased proliferation and increased vascular smooth muscle cell apoptosis in vitro and in vivo, reducing vascular remodeling while sparing healthy tissues after oral intake. Using pharmacological (agonists and antagonists of Akt and its downstream target glycogen-synthase-kinase-3␤ [GSK-3␤]) and molecular (forced expression of constitutively active Akt1) approaches, we showed that the effects of DHEA were mediated by inhibition of Akt and subsequent activation of GSK-3␤, leading to mitochondrial depolarization, increased reactive oxygen species, activation of redox-sensitive plasmalemmal voltage-gated K ϩ channels, and decreased [Ca 2ϩ ] i . These functional changes were accompanied by sustained molecular effects toward the same direction; by decreasing [Ca 2ϩ ] i and inhibiting GSK-3␤, DHEA inhibited the nuclear factor of activated T cells transcription factor, thus increasing expression of Kv channels (Kv1.5) and contributing to sustained mitochondrial depolarization. These results were independent of any steroidrelated effects because they were not altered by androgen and estrogen inhibitors but involved a membrane G protein-coupled receptor. Conclusions-We suggest that the orally available DHEA might be an attractive candidate for the treatment of systemic vascular remodeling, including restenosis, and we propose a novel mechanism of action for this important hormone and

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“…Growth factors, such as platelet-derived growth factor and epidermal growth factor, have been shown to increase cell proliferation by increasing both basal G6PD activity and G6PD expression (19). Deficient G6PD activity is associated with decreased cell proliferation in both steroid receptor-positive and receptor-negative breast cancer cell lines (20), COS-7 cells, Swiss 3T3, Balb/c 3T3, and A31 fibroblasts (19). In contrast, increased G6PD expression enhances cell proliferation.…”

Section: G6pd Vegf and Angiogenesismentioning

confidence: 99%

“…The association between G6PD activity and cell proliferation has been well described in several non-vascular cell types (19,20). Growth factors, such as platelet-derived growth factor and epidermal growth factor, have been shown to increase cell proliferation by increasing both basal G6PD activity and G6PD expression (19).…”

Section: G6pd Vegf and Angiogenesismentioning

confidence: 99%

Glucose-6-phosphate Dehydrogenase Modulates Vascular Endothelial Growth Factor-mediated Angiogenesis

Leopold

Walker

Scribner

et al. 2003

Journal of Biological Chemistry

145

125

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Glucose-6-phosphate dehydrogenase (G6PD), the first enzyme of the pentose phosphate pathway, is the principal intracellular source of NADPH. NADPH is utilized as a cofactor by vascular endothelial cell nitric-oxide synthase (eNOS) to generate nitric oxide (NO ⅐ ). To determine whether G6PD modulates NO ⅐ -mediated angiogenesis, we decreased G6PD expression in bovine aortic endothelial cells using an antisense oligodeoxynucleotide to G6PD or increased G6PD expression by adenoviral gene transfer, and we examined vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation, migration, and capillary-like tube formation. Deficient G6PD activity was associated with a significant decrease in endothelial cell proliferation, migration, and tube formation, whereas increased G6PD activity promoted these processes. VEGF-stimulated eNOS activity and NO ⅐ production were decreased significantly in endothelial cells with deficient G6PD activity and enhanced in G6PD-overexpressing cells. In addition, G6PD-deficient cells demonstrated decreased tyrosine phosphorylation of the VEGF receptor Flk-1/ KDR, Akt, and eNOS compared with cells with normal G6PD activity, whereas overexpression of G6PD enhanced phosphorylation of Flk-1/KDR, Akt, and eNOS. In the Pretsch mouse, a murine model of G6PD deficiency, vessel outgrowth from thoracic aorta segments was impaired compared with C3H wild-type mice. In an in vivo Matrigel angiogenesis assay, cell migration into the plugs was inhibited significantly in G6PD-deficient mice compared with wild-type mice, and gene transfer of G6PD restored the wild-type phenotype in G6PD-deficient mice. These findings demonstrate that G6PD modulates angiogenesis and may represent a novel angiogenic regulator.

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Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells

Cited by 58 publications

References 24 publications

Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity

Dehydroepiandrosterone protects bovine retinal capillary pericytes against glucose toxicity

Dehydroepiandrosterone Reverses Systemic Vascular Remodeling Through the Inhibition of the Akt/GSK3-β/NFAT Axis

Glucose-6-phosphate Dehydrogenase Modulates Vascular Endothelial Growth Factor-mediated Angiogenesis

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