Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines

Yoshida, Shigemasa; Honda, Akira; Matsuzaki, Yasushi; Fukushima, Sugano; Tanaka, Naomi; Takagiwa, Aya; Fujimoto, Yoshinori; Miyazaki, Hiroshi; Salen, Gerald

doi:10.1016/s0039-128x(02)00117-4

Cited by 60 publications

(46 citation statements)

References 44 publications

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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: 81%

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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Section: Discussionmentioning

confidence: 81%

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

et al. 2009

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“…On day 0, cells were seeded in 100¿20 mm dishes at a density of 1.0∫10 7 cells per dish. On day 1, various concentrations of retinoic acid dissolved in ethanol (Yoshida et al 2003) were added to the medium (0.1, 1 and 10 mM final concentration in the medium). The same volume of ethanol was added to the controls.…”

Section: Methodsmentioning

confidence: 99%

All‐trans Retinoic Acid Induction of Sulfotransferases

Maiti¹,

Chen²,

Chen³

2005

Basic Clin Pharma Tox

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All-trans retinoic acid is the bioactive form of vitamin A (retinol). Retinoids have been used clinically as therapeutic agents against a number of cancers. Retinoids have been reported to induce the phase I drug metabolizing enzymes, cytochrome P-450s. In contrast, effects of retinoids on sulfotransferases have not been as well studied. The present investigation evaluates the role of retinoic acid on the expression of aryl sulfotransferase IV and hydroxysteroid sulfotransferase a in male and female Sprague-Dawley rat liver and intestine. Cultured human hepatic carcinoma cells (Hep G2) and intestinal carcinoma cells (Caco-2) were also used to study retinoic acid's effect on simple phenol sulfating sulfotransferase, dehydroepiandrosterone sulfotransferase and oestrogen sulfotransferase. Enzyme assay and Western blot were used to determine sulfotransferase protein expression. Retinoic acid induced aryl sulfotransferase IV in liver of female rats and sulfotransferase a in liver of male rats. Intestinal rat aryl sulfotransferase IV and sulfotransferase a in male rats and intestinal aryl sulfotransferase IV in female rats were also induced after retinoic acid treatment. In Hep G2 and Caco-2 cells, retinoic acid differentially induced the three human sulfotransferase isoforms. In general, intestinal sulfotransferases were found to be more responsive than hepatic sulfotransferases to retinoic acid treatment. mRNA expressions were investigated using reverse transcription polymerase chain reaction with gene specific primers. Reverse transcription polymerase chain reaction results are in good agreement with enzyme activity and Western blot results. This suggests that retinoic acid induction of sulfotransferases is at the transcriptional level.

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“…• C in a humidified atmosphere containing 5% CO 2 (Qiao et al, 1996;Yoshida et al, 2003). The media containing the cells were transferred into a 96-well microplate at a rate of 2500 cells per well and incubated overnight at 37…”

Section: Inhibition Of Caco-2 Colon Cancer Cell Proliferationmentioning

confidence: 99%

Antioxidant and Antiproliferative Potential of Pearled Barley (Hordeum vulgarae.)

Madhujith

Shahidi

2008

Pharmaceutical Biology

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Two barley varieties, Falcon and AC Metcalfe, were separated by pearling into seven fractions. Each fraction was subsequently extracted with 80% methanol. Total phenolic content of the extracts so obtained was determined by the Folin-Ciocalteu method and ranged from 0.51 to 6.26 and 0.17 to 4.16 mg ferulic acid equiv/g defatted material, respectively. In both barley varieties, the outermost fraction (F1) yielded the highest phenolic content. The extracts were evaluated for their efficacy in scavenging of peroxyl and hydroxyl radicals using electron paramagnetic resonance (EPR). IC 50 value, an indicator of efficacy of a test extract in reducing radical concentration by 50%, ranged from 3.51 to 3.71 mg/mL and 0.27 to 0.51 mg/mL for peroxyl radical for Falcon and AC Metcalfe fraction extracts, respectively. The corresponding values for hydroxyl radical ranged from 0.51 to 3.30 mg/mL and 0.68 to 3.75 mg/mL. Metal chelation activity was determined using the 2,2 -bipyridyl competition assay. Effectiveness of phenolic extracts in inhibiting radical-induced supercoiled DNA breakage was also evaluated. Finally, the potential of phenolic extracts in inhibiting the growth of Caco-2 human adenocarcinoma cells was determined. Barley fractions showed a high level of antiproliferative activity toward inhibition of Caco-2 human colorectal adenocarcinoma cells. Percentage inhibition of cancer cells rendered by Falcon and AC Metcalfe barley fraction extracts ranged from 14% to 74% and 21% to 57%, respectively, at 0.5 mg/mL concentration. The results indicate that barley fractions tested possess significant antioxidant and antiproliferative activities.

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Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines

Cited by 60 publications

References 44 publications

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

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

All‐trans Retinoic Acid Induction of Sulfotransferases

Antioxidant and Antiproliferative Potential of Pearled Barley (Hordeum vulgarae.)

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