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Zhang Y, Cheng Y, Qin L, Liu Y, Huang S, Dai L, Tao J, Pan J, Su C, Zhang Y. Plasma metabolomics for the assessment of the progression of non-small cell lung cancer. Int J Biol Markers 2022; 38:37-45. [PMID: 36377344 DOI: 10.1177/03936155221137359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objectives Non-small cell lung cancer (NSCLC) is a leading type of lung cancer with a high mortality rate worldwide. Although many procedures for the diagnosis and prognosis assessment of lung cancer exist, they are often laborious, expensive, and invasive. This study aimed to develop an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS)-based analysis method for the plasma biomarkers of NSCLC with the potential to indicate the stages and progression of this malignancy conveniently and reliably. Methods A total of 53 patients with NSCLC in early stages (I–III) and advanced stage (IV) were classified into the early and advanced groups based on the tumor node metastasis staging system. A comprehensive metabolomic analysis of plasma from patients with NSCLC was performed via UPLC–MS/MS. Principal component analysis and partial least squares–discriminant analysis were conducted for statistical analysis. Potential biomarkers were evaluated and screened through receiver operating characteristic analyses and correlation analysis. Main differential metabolic pathways were also identified by utilizing metaboanalyst. Results A total of 129 differential metabolites were detected in accordance with the criteria of VIP ≥ 1 and a P-value of ≤ 0.05. The receiver operating characteristic curves indicated that 11 of these metabolites have the potential to be promising markers of disease progression. Apparent correlated metabolites were also filtered out. Furthermore, the 11 most predominant metabolic pathways with alterations involved in NSCLC were identified. Conclusion Our study focused on the plasma metabolomic changes in patients with NSCLC. These changes may be used for the prediction of the stage and progression of NSCLC. Moreover, we discussed the metabolic pathways wherein the altered metabolites were mainly enriched.
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Affiliation(s)
- Yingtian Zhang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Yaping Cheng
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Liqiang Qin
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, Jiangsu, PR China
| | - Yuanliang Liu
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Sijia Huang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Liya Dai
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Jialong Tao
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Jie Pan
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Cunjin Su
- Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
| | - Yusong Zhang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, PR China
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2
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Whitburn J, Rao SR, Morris EV, Tabata S, Hirayama A, Soga T, Edwards JR, Kaya Z, Palmer C, Hamdy FC, Edwards CM. Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival. SCIENCE ADVANCES 2022; 8:eabf9096. [PMID: 35213227 PMCID: PMC8880772 DOI: 10.1126/sciadv.abf9096] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.
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Affiliation(s)
- Jessica Whitburn
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Srinivasa R. Rao
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Emma V. Morris
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Sho Tabata
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - James R. Edwards
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Zeynep Kaya
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Charlotte Palmer
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Freddie C. Hamdy
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Claire M. Edwards
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Corresponding author.
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Zarei I, Oppel RC, Borresen EC, Brown RJ, Ryan EP. Modulation of plasma and urine metabolome in colorectal cancer survivors consuming rice bran. ACTA ACUST UNITED AC 2019; 6. [PMID: 31396400 DOI: 10.15761/ifnm.1000252] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Rice bran has bioactive phytochemicals with cancer protective actions that involve metabolism by the host and the gut microbiome. Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and the increased incidence is largely attributed to poor dietary patterns, including low daily fiber intake. A dietary intervention trial was performed to investigate the impact of rice bran consumption on the plasma and urine metabolome of CRC survivors. Nineteen CRC survivors participated in a randomized-controlled trial that included consumption of heat-stabilized rice bran (30 g/day) or a control diet without rice bran for 4 weeks. A fasting plasma and first void of the morning urine sample were analyzed by non-targeted metabolomics using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After 4 weeks of either rice bran or control diets, 12 plasma and 16 urine metabolites were significantly different between the groups (p≤0.05). Rice bran intake increased relative abundance of plasma mannose (1.373-fold) and beta-citrylglutamate (BCG) (1.593-fold), as well as increased urine N-formylphenylalanine (2.191-fold) and dehydroisoandrosterone sulfate (DHEA-S) (4.488-fold). Diet affected metabolites, such as benzoate, mannose, eicosapentaenoate (20:5n3) (EPA), and N-formylphenylalanine have been previously reported for cancer protection and were identified from the rice bran food metabolome. Nutritional metabolome changes following increased consumption of whole grains such as rice bran warrants continued investigation for colon cancer control and prevention attributes as dietary biomarkers for positive effects are needed to reduce high risk for colorectal cancer recurrence.
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Affiliation(s)
- Iman Zarei
- Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA
| | - Renee C Oppel
- Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA
| | - Erica C Borresen
- Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA
| | - Regina J Brown
- University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Elizabeth P Ryan
- Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, 80523, USA
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Hashimoto R, Gupte S. Pentose Shunt, Glucose-6-Phosphate Dehydrogenase, NADPH Redox, and Stem Cells in Pulmonary Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 967:47-55. [PMID: 29047080 DOI: 10.1007/978-3-319-63245-2_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Redox signaling plays a critical role in the pathophysiology of cardiovascular diseases. The pentose phosphate pathway is a major source of NADPH redox in the cell. The activities of glucose-6-phosphate dehydrogenase (the rate-limiting enzyme in the pentose shunt) and glucose flux through the shunt pathway is increased in various lung cells including, the stem cells, in pulmonary hypertension. This chapter discusses the importance of the shunt pathway and glucose-6-phosphate dehydrogenase in the pathogenesis of pulmonary artery remodeling and occlusive lesion formation within the hypertensive lungs.
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Affiliation(s)
- Ryota Hashimoto
- Department of Pharmacology, New York Medical College, School of Medicine, Basic Science Building, Rm. 546, 15 Dana Road, Valhalla, NY, 10595, USA
| | - Sachin Gupte
- Department of Pharmacology, New York Medical College, School of Medicine, Basic Science Building, Rm. 546, 15 Dana Road, Valhalla, NY, 10595, USA.
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miR-1 inhibits progression of high-risk papillomavirus-associated human cervical cancer by targeting G6PD. Oncotarget 2018; 7:86103-86116. [PMID: 27861141 PMCID: PMC5349900 DOI: 10.18632/oncotarget.13344] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 11/08/2016] [Indexed: 12/16/2022] Open
Abstract
Ectopic glucose-6-phosphate dehydrogenase (G6PD) expression may contribute to tumorigenesis in cervical cancer associated with high-risk human papillomavirus (HR-HPV 16 and 18) infections. Here, we demonstrate that microRNA-1 (miR-1) in association with AGO proteins targets G6PD in HR-HPV-infected human cervical cancer cells. miR-1 inhibited expression of a reporter construct containing a putative G6PD 3′-UTR seed region and suppressed endogenous G6PD expression. Down-regulation of miR-1 increased G6PD expression in cervical cancer cells. Regression analysis revealed that miR-1 levels correlate negatively with the clinicopathologic features in HR-HPV 16/18-infected cervical cancer patients. miR-1 overexpression inhibited proliferation and promoted apoptosis in cervical cancer cells and reduced xenograft tumor growth in nude mice. Conversely, sponge-mediated miR-1 knockdown markedly increased viability and reduced apoptosis in cervical cancer cells and supported neoplasm growth. Restoration of G6PD expression partially reversed the effects of miR-1 overexpression both in vitro and in vivo. In addition, co-transfection of G6PD siRNA and miR-1 sponge partially reversed miR-1 sponge-induced reductions in cell viability and neoplasm growth. These results suggest that miR-1 suppresses the development and progression of HR-HPV 16/18-infected cervical cancer by targeting G6PD and may be a promising novel therapeutic candidate.
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D'Alessandro A, El Kasmi KC, Plecitá-Hlavatá L, Ježek P, Li M, Zhang H, Gupte SA, Stenmark KR. Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming. Antioxid Redox Signal 2018; 28. [PMID: 28637353 PMCID: PMC5737722 DOI: 10.1089/ars.2017.7217] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SIGNIFICANCE The molecular events that promote the development of pulmonary hypertension (PH) are complex and incompletely understood. The complex interplay between the pulmonary vasculature and its immediate microenvironment involving cells of immune system (i.e., macrophages) promotes a persistent inflammatory state, pathological angiogenesis, and fibrosis that are driven by metabolic reprogramming of mesenchymal and immune cells. Recent Advancements: Consistent with previous findings in the field of cancer metabolism, increased glycolytic rates, incomplete glucose and glutamine oxidation to support anabolism and anaplerosis, altered lipid synthesis/oxidation ratios, increased one-carbon metabolism, and activation of the pentose phosphate pathway to support nucleoside synthesis are but some of the key metabolic signatures of vascular cells in PH. In addition, metabolic reprogramming of macrophages is observed in PH and is characterized by distinct features, such as the induction of specific activation or polarization states that enable their participation in the vascular remodeling process. CRITICAL ISSUES Accumulation of reducing equivalents, such as NAD(P)H in PH cells, also contributes to their altered phenotype both directly and indirectly by regulating the activity of the transcriptional co-repressor C-terminal-binding protein 1 to control the proliferative/inflammatory gene expression in resident and immune cells. Further, similar to the role of anomalous metabolism in mitochondria in cancer, in PH short-term hypoxia-dependent and long-term hypoxia-independent alterations of mitochondrial activity, in the absence of genetic mutation of key mitochondrial enzymes, have been observed and explored as potential therapeutic targets. FUTURE DIRECTIONS For the foreseeable future, short- and long-term metabolic reprogramming will become a candidate druggable target in the treatment of PH. Antioxid. Redox Signal. 28, 230-250.
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Affiliation(s)
- Angelo D'Alessandro
- 1 Department of Biochemistry and Molecular Genetics, University of Colorado - Denver , Colorado
| | - Karim C El Kasmi
- 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, University of Colorado - Denver , Colorado.,3 Department of Pediatric Gastroenterology, University of Colorado - Denver , Colorado
| | - Lydie Plecitá-Hlavatá
- 4 Department of Mitochondrial Physiology, Institute of Physiology , Czech Academy of Sciences, Prague, Czech Republic
| | - Petr Ježek
- 4 Department of Mitochondrial Physiology, Institute of Physiology , Czech Academy of Sciences, Prague, Czech Republic
| | - Min Li
- 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, University of Colorado - Denver , Colorado
| | - Hui Zhang
- 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, University of Colorado - Denver , Colorado
| | - Sachin A Gupte
- 5 Department of Pharmacology, School of Medicine, New York Medical College , Valhalla, New York
| | - Kurt R Stenmark
- 2 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, University of Colorado - Denver , Colorado
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Brahimaj A, Muka T, Kavousi M, Laven JSE, Dehghan A, Franco OH. Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study. Diabetologia 2017; 60:98-106. [PMID: 27771738 PMCID: PMC6518366 DOI: 10.1007/s00125-016-4136-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 09/26/2016] [Indexed: 12/22/2022]
Abstract
AIMS/HYPOTHESIS Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes. METHODS We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l. RESULTS During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio. CONCLUSIONS/INTERPRETATION DHEA serum levels might be an independent marker of type 2 diabetes.
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Affiliation(s)
- Adela Brahimaj
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
| | - Taulant Muka
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands
| | - Maryam Kavousi
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands
| | - Joop S E Laven
- Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, the Netherlands
| | - Abbas Dehghan
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands
| | - Oscar H Franco
- Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands
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Cheng ML, Chi LM, Wu PR, Ho HY. Dehydroepiandrosterone-induced changes in mitochondrial proteins contribute to phenotypic alterations in hepatoma cells. Biochem Pharmacol 2016; 117:20-34. [DOI: 10.1016/j.bcp.2016.08.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 08/04/2016] [Indexed: 10/21/2022]
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Coda DM, Lingua MF, Morena D, Foglizzo V, Bersani F, Ala U, Ponzetto C, Taulli R. SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma. Cell Cycle 2016; 14:1389-402. [PMID: 25644430 DOI: 10.1080/15384101.2015.1005993] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Rhadomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS cells resemble fetal myoblasts but are unable to complete myogenic differentiation. In previous work we showed that miR-206, which is low in RMS, when induced in RMS cells promotes the resumption of differentiation by modulating more than 700 genes. To better define the pathways involved in the conversion of RMS cells into their differentiated counterpart, we focused on 2 miR-206 effectors emerged from the microarray analysis, SMYD1 and G6PD. SMYD1, one of the most highly upregulated genes, is a H3K4 histone methyltransferase. Here we show that SMYD1 silencing does not interfere with the proliferative block or with the loss anchorage independence imposed by miR-206, but severely impairs differentiation of ERMS, ARMS, and myogenic cells. Thus SMYD1 is essential for the activation of muscle genes. Conversely, among the downregulated genes, we found G6PD, the enzyme catalyzing the rate-limiting step of the pentose phosphate shunt. In this work, we confirmed that G6PD is a direct target of miR-206. Moreover, we showed that G6PD silencing in ERMS cells impairs proliferation and soft agar growth. However, G6PD overexpression does not interfere with the pro-differentiating effect of miR-206, suggesting that G6PD downmodulation contributes to - but is not an absolute requirement for - the tumor suppressive potential of miR-206. Targeting cancer metabolism may enhance differentiation. However, therapeutic inhibition of G6PD is encumbered by side effects. As an alternative, we used DCA in combination with miR-206 to increase the flux of pyruvate into the mitochondrion by reactivating PDH. DCA enhanced the inhibition of RMS cell growth induced by miR-206, and sustained it upon miR-206 de-induction. Altogether these results link miR-206 to epigenetic and metabolic reprogramming, and suggest that it may be worth combining differentiation-inducing with metabolism-directed approaches.
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Key Words
- DCA, Dichloroacetate
- DHEA, Dehydroepiandrosterone
- G6PD, Glucose 6 Phosphate Dehydrogenase
- HMT, Histone MethylTransferase
- MREs, MicroRNA Responsive Elements
- MRFs, Myogenic Regulatory Factors
- PDH, Pyruvate Dehydrogenase
- PDK, Pyruvate Dehydrogenase Kinase
- PPP, Pentose Phosphate Pathway
- RMS, Rhabdomyosarcoma
- Rhabdomyosarcoma
- SMYD1, SET and MYND domain-containing protein 1
- TCA cycle, TriCarboxylic Acid cycle
- differentiation therapy
- metabolism and cancer
- miR-206
- myomiRs, muscle-specific microRNAs
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Samaras N, Papadopoulou MA, Samaras D, Ongaro F. Off-label use of hormones as an antiaging strategy: a review. Clin Interv Aging 2014; 9:1175-86. [PMID: 25092967 PMCID: PMC4116364 DOI: 10.2147/cia.s48918] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Given demographic evolution of the population in modern societies, one of the most important health care needs is successful aging with less frailty and dependency. During the last 20 years, a multitude of anti-aging practices have appeared worldwide, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. At present, women live one third of their lives in a state of sex-hormone deficiency. Men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, growth hormone age-associated decrease may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and actual use of hormone supplements in aging and elderly patients. In this article, we review actual data on the effects of age related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity. We also provide information on the efficiency and safety of hormone replacement protocols in aging patients. Finally, we argue on future perspectives of such protocols as part of everyday practice.
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Affiliation(s)
| | | | - Dimitrios Samaras
- Department of Medical Specialties, Clinical Nutrition, Geneva University Hospitals, Geneva, Switzerland
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Samaras N, Samaras D, Frangos E, Forster A, Philippe J. A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: is treatment beneficial? Rejuvenation Res 2014; 16:285-94. [PMID: 23647054 DOI: 10.1089/rej.2013.1425] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant steroids in humans. DHEA levels fall with age in men and women, reaching values sometimes as low as 10%-20% of those encountered in young individuals. This age-related decrease suggests an "adrenopause" phenomenon. Studies point toward several potential roles of DHEA, mainly through its hormonal end products, making this decline clinically relevant. Unfortunately, even if positive effects of DHEA on muscle, bone, cardiovascular disease, and sexual function seem rather robust, extremely few studies are large enough and/or long enough for conclusions regarding its effects on aging. Moreover, because it has been publically presented as a "fountain of youth" equivalent, over-the-counter preparations lacking pharmacokinetic and pharmacodynamic data are widely used worldwide. Conceptually, supplementing a pre-hormone is extremely interesting, because it would permit the human organism to adequately use it throughout long periods, increasing or decreasing end products according to his needs. Nevertheless, data on the safety profile of long-term DHEA supplementation are still lacking. In this article, we examine the potential relation between low DHEA levels and well-known age-related diseases, such as sarcopenia, osteoporosis, dementia, sexual disorders, and cardiovascular disease. We also review risks and benefits of existing protocols of DHEA supplementation.
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Affiliation(s)
- Nikolaos Samaras
- Department of Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.
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Galdo M, Gregonis J, Fiore CS, Compagnone NA. Dehydroepiandrosterone biosynthesis, role, and mechanism of action in the developing neural tube. Front Endocrinol (Lausanne) 2012; 3:16. [PMID: 22649409 PMCID: PMC3355923 DOI: 10.3389/fendo.2012.00016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 01/19/2012] [Indexed: 12/19/2022] Open
Abstract
Dehydroepiandrosterone (DHEA) is synthesized from cholesterol by activity of P450scc and P450c17, enzymes that we previously characterized in the developing nervous system. We describe the localization of P450c17 in the differentiated field of the ventral spinal cord in different motor neuron subtypes. We show that, during organogenesis, P450c17 activity is regulated along the antero/posterior axis of the spinal cord concomitantly with the gradient of neurogenesis. To examine whether DHEA may modulate this process, we measured proliferation and differentiation of ventral neural precursors in primary and explant cultures. Our results showed that DHEA-induced the expression of class II protein Nkx6.1, motor neuron precursor Olig-2, and definitive motor neuron marker Isl-1/2. DHEA also promoted proliferation of ventrally committed precursors in isolated spinal cord precursor cultures and in whole spinal cord explants. Both the proliferative and inductive effects of DHEA were dependent on sonic hedgehog signaling. The possibilities that the effects observed with DHEA were due to its metabolism into androgens or to activation of NMDA receptors were excluded. These results support the hypothesis that the tight regulation of DHEA biosynthesis may be a biologic clock restricting the period of ventral neuronal-precursor proliferation, thus controlling the number of pre-committed neurons in the developing neural tube.
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Affiliation(s)
- Mark Galdo
- Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of CaliforniaSan Francisco, CA, USA
| | - Jennifer Gregonis
- Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of CaliforniaSan Francisco, CA, USA
| | - Christelle S. Fiore
- Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of CaliforniaSan Francisco, CA, USA
| | - Nathalie A. Compagnone
- Laboratory for Spinal Cord Development and Regeneration, Department of Neurological Surgery, University of CaliforniaSan Francisco, CA, USA
- *Correspondence: Nathalie A. Compagnone, Innovative Concepts in Drug Development, Innovation Park Michel Caucik, BP2 100 rte des houilleres, 13590 Meyreuil, France. e-mail:
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Girón RA, Montaño LF, Escobar ML, López-Marure R. Dehydroepiandrosterone inhibits the proliferation and induces the death of HPV-positive and HPV-negative cervical cancer cells through an androgen- and estrogen-receptor independent mechanism. FEBS J 2009; 276:5598-609. [PMID: 19702826 DOI: 10.1111/j.1742-4658.2009.07253.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Dehydroepiandrosterone (DHEA) has a protective role against epithelial-derived carcinomas; however, the mechanisms remain unknown. We determined the effect of DHEA on cell proliferation, the cell cycle and cell death in three cell lines derived from human uterine cervical cancers infected or not with human papilloma virus (HPV). We also determined whether DHEA effects are mediated by estrogen and androgen receptors. Proliferation of C33A (HPV-negative), CASKI (HPV16-positive) and HeLa (HPV18-positive) cells was evaluated by violet crystal staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction. Flow cytometry was used to evaluate the phases of the cell cycle, and cell death was detected using a commercially available carboxyfluorescein apoptosis detection kit that determines caspase activation. DNA fragmentation was determined using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Flutamide and ICI 182,780 were used to inhibit androgen and estrogen receptors, respectively, and letrozol was used to inhibit the conversion of DHEA to estradiol. Our results show that DHEA inhibited cell proliferation in a dose-dependent manner in the three cell lines; the DHEA IC(50) doses were 50, 60 and 70 mum for C33A, CASKI and HeLa cells, respectively. The antiproliferative effect was not abrogated by inhibitors of androgen and estrogen receptors or by an inhibitor of the conversion of testosterone to estradiol, and this effect was associated with an increase in necrotic cell death in HPV-negative cells and apoptosis in HPV-positive cells. These results suggest that DHEA strongly inhibits the proliferation of cervical cancer cells, but its effect is not mediated by androgen or estrogen receptor pathways. DHEA could therefore be used as an alternative in the treatment of cervical cancer.
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Affiliation(s)
- Roma A Girón
- Departamento de Biología Celular, Instituto Nacional de Cardiología 'Ignacio Chávez', México DF, México
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14
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Burgess JP, Green JS, Hill JM, Zhan Q, Lindeblad M, Lyubimov A, Kapetanovic IM, Schwartz A, Thomas BF. Identification of [14C]fluasterone metabolites in urine and feces collected from dogs after subcutaneous and oral administration of [14C]fluasterone. Drug Metab Dispos 2009; 37:1089-97. [PMID: 19196848 PMCID: PMC2683393 DOI: 10.1124/dmd.108.023614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2008] [Accepted: 01/29/2009] [Indexed: 11/22/2022] Open
Abstract
The objective of this research was the identification of the metabolic profile of fluasterone, a synthetic derivative of dehydroepiandrosterone, in dogs treated orally or subcutaneously with [4-(14)C]fluasterone. Separation and characterization techniques used to identify the principal metabolites of fluasterone in urine and feces included high-performance liquid chromatography (HPLC), liquid scintillation spectrometry, HPLC/tandem mass spectrometry, and NMR. In urine, the majority of the radioactivity was present as two components that had apparent molecular weights consistent with their tentative identification as monoglucuronide conjugates of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol and X(alpha or beta)-4alpha-dihydroxy-16alpha-fluoro-5-androsten-17beta-ol. The identification of the monoglucuronide conjugate of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol was also supported by NMR data. In support of this identification, these metabolites were cleaved with glucuronidase enzyme treatment, which gave rise to components with molecular weights again consistent with the aglycones of a monohydroxylated, 17-keto reduced (dihydroxy) fluasterone metabolite and a dihydroxylated, 17-keto reduced (trihydroxy) fluasterone metabolite. In feces, nonconjugated material predominated. The primary metabolites eliminated in feces were the two hydroxy fluasterone metabolites arising from 17-reduction (16alpha-fluoro-5-androsten-17beta-ol and 16alpha-fluoro-5-androsten-17alpha-ol) and 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol that was present in urine in glucuronide form.
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Affiliation(s)
- Jason P Burgess
- Analytical Chemistry and Pharmaceutics Group, RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA
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15
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Arnold JT. DHEA metabolism in prostate: For better or worse? Mol Cell Endocrinol 2009; 301:83-8. [PMID: 19013497 PMCID: PMC2667103 DOI: 10.1016/j.mce.2008.10.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2008] [Revised: 10/14/2008] [Accepted: 10/15/2008] [Indexed: 11/16/2022]
Abstract
Dehydroepiandrosterone (DHEA) is commonly used in the USA as a nutritional supplement for antiaging, metabolic support or other uses. Investigations into understanding the effects of DHEA on human prostate cancer progression have posed more questions than answers and highlight the importance of communications between stromal and epithelial tuoitiuot elements within the prostate that contribute to the regulation of DHEA metabolism. Intracrine metabolism of DHEA to androgens (A) and/or estrogens (E) may occur in one cell compartment (stromal) which may release paracrine hormones or growth/inhibitory factors to the epithelial cells. Alternatively no metabolism of DHEA may occur, resulting in no harmful consequences of high levels of DHEA in prostate tissues. We herein review the tissue components involved and interactions with the prohormone, DHEA and/or resulting metabolites, including dihydrotestosterone (DHT) or 17beta-estradiol (E(2)) in an in vitro model of endocrine-immune-paracrine interactions within the prostate. This work raises questions and hypotheses concerning the role of DHEA in prostate in normal tissues, vs. preneoplastic tissues.
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Affiliation(s)
- Julia T Arnold
- LCI-Endocrine Section, National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health (NIH), Building 10/2B47 MSC 1547, 9000 Rockville Pike, Bethesda, MD 20892-1547, USA.
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16
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Yamakawa T, Ogihara K, Nakamura M, Utsunomiya H, Kadonosono K, Kishikawa S, Terauchi Y. Effect of Dehydroepiandrosterone on Atherosclerosis in Apolipoprotein E-Deficient Mice. J Atheroscler Thromb 2009; 16:501-8. [DOI: 10.5551/jat.no618] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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17
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Al-Mutairi DA, Craik JD, Batinic-Haberle I, Benov LT. Inactivation of metabolic enzymes by photo-treatment with zinc meta N-methylpyridylporphyrin. Biochim Biophys Acta Gen Subj 2007; 1770:1520-7. [PMID: 17884296 DOI: 10.1016/j.bbagen.2007.06.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Revised: 06/10/2007] [Accepted: 06/13/2007] [Indexed: 11/25/2022]
Abstract
Cell proliferation is notably dependent on energy supply and generation of reducing equivalents in the form of NADPH for reductive biosynthesis. Blockage of pathways generating energy and reducing equivalents has proved successful for cancer treatment. We have previously reported that isomeric Zn(II) N-methylpyridylporphyrins (ZnTM-2(3,4)-PyP4+) can act as photosensitizers, preventing cell proliferation and causing cell death in vitro. The present study demonstrates that upon illumination, ZnTM-3-PyP inactivates glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, lactate dehydrogenase, NADP+ -linked isocitrate dehydrogenase, aconitase, and fumarase in adenocarcinoma LS174T cells. ZnTM-3-PyP4+ was significantly more effective than hematoporphyrin derivative (HpD) for inactivation of all enzymes, except aconitase and isocitrate dehydrogenase. Enzyme inactivation was accompanied by aggregation, presumably due to protein cross-linking of some of the enzymes tested. Inactivation of metabolic enzymes caused disruption of cancer cells' metabolism and is likely to be one of the major reasons for antiproliferative activity of ZnTM-3-PyP.
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Affiliation(s)
- Dalal A Al-Mutairi
- Department of Biochemistry, Faculty of Medicine, Kuwait University, PO Box 24923 Safat, 13110, Kuwait
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18
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Oka M, Karoor V, Homma N, Nagaoka T, Sakao E, Golembeski SM, Limbird J, Imamura M, Gebb SA, Fagan KA, McMurtry IF. Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension. Cardiovasc Res 2007; 74:377-87. [PMID: 17346686 PMCID: PMC1950784 DOI: 10.1016/j.cardiores.2007.01.021] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Revised: 01/25/2007] [Accepted: 01/31/2007] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE It has been reported that dehydroepiandrosterone is a pulmonary vasodilator and inhibits chronic hypoxia-induced pulmonary hypertension. Additionally, dehydroepiandrosterone has been shown to improve systemic vascular endothelial function. Thus, we hypothesized that chronic treatment with dehydroepiandrosterone would attenuate hypoxic pulmonary hypertension by enhancing pulmonary artery endothelial function. METHODS AND RESULTS Rats were randomly assigned to five groups. Three groups received food containing 0, 0.3, or 1% dehydroepiandrosterone during a 3-wk-exposure to simulated high altitude (HA). The other 2 groups were kept at Denver's low altitude (LA) and received food containing 0 or 1% dehydroepiandrosterone. Dehydroepiandrosterone dose-dependently inhibited hypoxic pulmonary hypertension (mean pulmonary artery pressures after treatment with 0, 0.3, and 1% dehydroepiandrosterone=45+/-5, 33+/-2*, and 25+/-1*# mmHg, respectively. *P<0.05 vs. 0% and # vs. 0.3%). Dehydroepiandrosterone (1%, 3 wks) treatment started after rats had been exposed to 3-wk hypoxia also effectively reversed established hypoxic pulmonary hypertension. Pulmonary artery rings isolated from both LA and HA rats treated with 1% dehydroepiandrosterone showed enhanced relaxations to acetylcholine and sodium nitroprusside, but not to 8-bromo-cGMP. In the pulmonary artery tissue from dehydroepiandrosterone-treated LA and HA rats, soluble guanylate cyclase, but not endothelial nitric oxide synthase, protein levels were increased. CONCLUSION These results indicate that the protective effect of dehydroepiandrosterone against hypoxic pulmonary hypertension may involve upregulation of pulmonary artery soluble guanylate cyclase protein expression and augmented pulmonary artery vasodilator responsiveness to nitric oxide.
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MESH Headings
- Acetylcholine/pharmacology
- Animals
- Blotting, Western
- Cyclic GMP/pharmacology
- Dehydroepiandrosterone/metabolism
- Dehydroepiandrosterone/therapeutic use
- Dehydroepiandrosterone Sulfate/blood
- Dehydroepiandrosterone Sulfate/metabolism
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Estradiol/blood
- Guanylate Cyclase/analysis
- Guanylate Cyclase/metabolism
- Hypertension, Pulmonary/blood
- Hypertension, Pulmonary/drug therapy
- Hypertension, Pulmonary/metabolism
- Hypoxia/metabolism
- In Vitro Techniques
- Lung/enzymology
- Male
- Muscle, Smooth, Vascular/metabolism
- Nitric Oxide/metabolism
- Nitric Oxide Synthase Type III/analysis
- Nitric Oxide Synthase Type III/antagonists & inhibitors
- Nitroprusside/pharmacology
- Pulmonary Artery/drug effects
- Pulmonary Artery/metabolism
- Pulmonary Artery/physiopathology
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/analysis
- Receptors, Cytoplasmic and Nuclear/metabolism
- Soluble Guanylyl Cyclase
- Testosterone/blood
- Up-Regulation
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Masahiko Oka
- Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver Colorado 80262, United States.
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19
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Abstract
Over the lifetime of the animal, there are many changes in the function of the body’s organ systems. In the gastrointestinal tract there is a general modest decline in the function of the esophagus, stomach, colon, pancreas and liver. In the small intestine, there may be subtle alterations in the intestinal morphology, as well as a decline in the uptake of fatty acids and sugars. The malabsorption may be partially reversed by aging glucagon-like peptide 2 (GLP2) or dexamethasone. Modifications in the type of lipids in the diet will influence the intestinal absorption of nutrients: for example, in mature rats a diet enriched with saturated as compared with polysaturated fatty acids will enhance lipid and sugar uptake, whereas in older animals the opposite effect is observed. Thus, the results of studies of the intestinal adaptation performed in mature rats does not necessarily apply in older animals. The age-associated malabsorption of nutrients that occurs with aging may be one of the several factors which contribute to the malnutrition that occurs with aging.
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20
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Arnold JT, Blackman MR. Does DHEA exert direct effects on androgen and estrogen receptors, and does it promote or prevent prostate cancer? Endocrinology 2005; 146:4565-7. [PMID: 16227445 DOI: 10.1210/en.2005-0901] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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21
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Arnold JT, Le H, McFann KK, Blackman MR. Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells. Am J Physiol Endocrinol Metab 2005; 288:E573-84. [PMID: 15536203 DOI: 10.1152/ajpendo.00454.2004] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Serum levels of the adrenal androgen dehydroepiandrosterone (DHEA) peak in men and women in the third decade of life and decrease progressively with age. Increasing numbers of middle-aged and older individuals consume over-the-counter preparations of DHEA, hoping it will retard aging by increasing muscle and bone mass and strength, decreasing fat, and improving immunologic and neurobehavioral functions. Because DHEA can serve as a precursor to more potent androgens and estrogens, like testosterone (T), dihydrotestosterone (DHT), and 17beta-estradiol (E2), supplemental DHEA use may pose a cancer risk in patients with nascent or occult prostate cancer. The steroid-responsive human LNCaP prostate cancer cells, containing a functional but mutated androgen receptor (AR), were used to compare effects of DHEA with those of T, DHT, and E2 on cell proliferation and protein and/or gene expression of AR, prostate-specific antigen (PSA), IGF-I, IGF-I receptor (IGF-IR), IGF-II, IGF-binding proteins-2, -3, and -5, (IGFBPs-2, -3, and -5), and estrogen receptor-beta (ERbeta). Cell proliferation assays revealed significant stimulation by all four steroids. DHEA- and E2-induced responses were similar but delayed and reduced compared with that of T and DHT. All four hormones increased gene and/or protein expression of PSA, IGF-IR, IGF-I, and IGFBP-2 and decreased that of AR, ERbeta, IGF-II, and IGFBP-3. There were no significant effects of hormone treatment on IGFBP-5 mRNA. DHEA and E2 responses were similar, and distinct from those of DHT and T, in time- and dose-dependent studies. Further studies of the mechanisms of DHEA effects on prostate cancer epithelial cells of varying AR status, as well as on prostate stromal cells, will be required to discern the implications of DHEA supplementation on prostatic health.
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Affiliation(s)
- Julia T Arnold
- Endocrine Section, Laboratory of Clinical Investigation, Division of Intramural Research, NCCAM, NIH, 9 Memorial Dr., Rm 1N105, Bethesda, MD 20892-0933, USA.
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22
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Abstract
Dehydroepiandrosterone (DHEA) and its sulfated ester are found in high concentrations in the plasma; however, their role in normal human physiology, other than as precursors for sex hormones, remains incompletely defined. Studies of rodent models have shown that these hormones have beneficial effects on a wide variety of conditions, such as diabetes, obesity, immune function, atherosclerosis, and many of the disorders associated with normal aging. However, rodents are not the best models to study the actions of these hormones because they have very little endogenous DHEA; thus, the doses given to these animals are usually suprapharmacological. Human studies have been performed to determine the potential beneficial effects of DHEA replacement in persons with low DHEA levels. Results have been conflicting. Human studies suggest a potential role for DHEA replacement in persons who have undergone adrenalectomy and possibly in the aging population. However, long-term studies assessing the benefits vs adverse effects must be done before DHEA replacement can be recommended.
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23
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Ciolino H, MacDonald C, Memon O, Dankwah M, Yeh GC. Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo. Int J Cancer 2003; 105:321-5. [PMID: 12704664 DOI: 10.1002/ijc.11075] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We investigated the effect of the steroid hormone dehydroepiandrosterone (DHEA) on the hepatic expression and activity of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2 and 1B1, in Sprague-Dawley rats. In animals fed DHEA at 200 or 400 mg/kg body weight every other day for 2 weeks prior to exposure to the aryl hydrocarbon dimethylbenz[a]anthracene (DMBA, 5 mg/kg), there was a dose-dependent decrease in hepatic CYP activity, as measured by ethoxyresorufin-O (EROD) assay, from 37.1 to 22.9 and 14.7 pmoles/min/10 microg microsomes, respectively. DHEA did not directly inhibit microsomal EROD activity, however, leading us to investigate its effects on enzyme expression. To test this, we examined protein and mRNA levels of the enzymes. Western blot for CYP1A1 and CYP1A2 showed that DHEA inhibited the increase in hepatic CYP1A1 and CYP1A2 enzyme levels that are normally induced by DMBA. DMBA-induced increase in expression of CYP1A1, CYP1A2 and CYP1B1 mRNA was similarly blunted in DHEA-treated animals. DHEA was also able to significantly reduce the basal expression of CYP1A1 and CYP1A2 but not of CYP1B1. These results indicate that DHEA regulates the expression and, hence, the activity of hepatic carcinogen-activating enzymes in vivo, and this may be an important mechanism of its chemopreventive activity.
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Affiliation(s)
- Henry Ciolino
- Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, National Cancer Institute at Frederick, Frederick, MD, USA.
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24
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Yorek MA, Coppey LJ, Gellett JS, Davidson EP, Bing X, Lund DD, Dillon JS. Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function. Am J Physiol Endocrinol Metab 2002; 283:E1067-75. [PMID: 12376336 DOI: 10.1152/ajpendo.00173.2002] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes.
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Affiliation(s)
- Mark A Yorek
- Veterans Affairs Medical Center, Diabetes Endocrinology Research Center, and Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52246, USA.
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25
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Abstract
In this review we summarize recent data on the use of phase 2 enzyme inducers as cancer chemopreventive agents in preclinical and clinical studies. These agents elevate the expression of genes involved in the detoxication of electrophiles and free radicals that contribute to carcinogenesis. Their mechanisms of action, efficacy and limitations are discussed. Particular attention is paid to isothiocyante and dithiolethione classes of agents, as these are the most developed.
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Affiliation(s)
- Ryan A Dick
- Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, 615 N. Wolfe St., Rm. 7032, Baltimore, MD 21205, USA
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26
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Offner H, Zamora A, Drought H, Matejuk A, Auci DL, Morgan EE, Vandenbark AA, Reading CL. A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE. J Neuroimmunol 2002; 130:128-39. [PMID: 12225895 DOI: 10.1016/s0165-5728(02)00214-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.
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MESH Headings
- Androstenes/metabolism
- Androstenes/pharmacology
- Androstenols/pharmacology
- Animals
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- Cell Division/drug effects
- Cell Division/immunology
- Dehydroepiandrosterone/analogs & derivatives
- Dehydroepiandrosterone/pharmacology
- Encephalomyelitis, Autoimmune, Experimental/drug therapy
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/physiopathology
- Female
- Immunoglobulin G/blood
- Immunoglobulin G/drug effects
- Immunosuppressive Agents/pharmacology
- Lymphocytes/drug effects
- Lymphocytes/immunology
- Male
- Mice
- Mice, Inbred Strains
- Multiple Sclerosis, Relapsing-Remitting/drug therapy
- Multiple Sclerosis, Relapsing-Remitting/immunology
- Multiple Sclerosis, Relapsing-Remitting/physiopathology
- Myelin Proteolipid Protein/immunology
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Sex Factors
- Tumor Necrosis Factor-alpha/drug effects
- Tumor Necrosis Factor-alpha/immunology
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Affiliation(s)
- Halina Offner
- Department of Neurology, Oregon Health and Science University, 97201, Portland, OR, USA.
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27
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Hiroi N, Ichijo T, Ueshiba H, Miyachi Y. Intranasal administration of adrenocorticotropin-(1-24) stimulates adrenocortical hormone secretion. J Clin Endocrinol Metab 2002; 87:1750-3. [PMID: 11932311 DOI: 10.1210/jcem.87.4.8399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
To determine the efficiency of transmucosal absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1-24) (250 microg) in 12 healthy adult men (mean age, 24.3 +/- 3.2 yr; range, 21-31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1-24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 +/- 39.2% and 147.2 +/- 50.5%, respectively, peaking 30 min after ACTH-(1-24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1-24), DHEA increased by 49.1 +/- 27.2% and 81.6 +/- 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH-(1-24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1-24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement.
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Affiliation(s)
- Naoki Hiroi
- First Department of Internal Medicine, Toho University School of Medicine, Tokyo 143-0015, Japan.
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28
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Balcombe NR, Sinclair A. Ageing: definitions, mechanisms and the magnitude of the problem. Best Pract Res Clin Gastroenterol 2001; 15:835-49. [PMID: 11866480 DOI: 10.1053/bega.2001.0244] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
All multi-cellular organisms undergo change with time. Conception heralds the onset of growth and development, leading to reproductive competence and propagation of the species. With time, organisms age, leading to death as a final end-point. Whilst our knowledge and definitions of growth and reproduction are firmly established, the concept of ageing remains less well understood. One of the reasons for the lack of a singular definition of ageing is that it can be considered in many different ways, according to social, behavioural, physiological, morphological, cellular and molecular changes. Research has led to a number of theories being proposed that may explain the ageing process. In this chapter, we will review some of these theories and address some of the following fundamental questions: What is ageing? How can ageing be measured? When does ageing begin? When is an organism defined as old?
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Affiliation(s)
- N R Balcombe
- Section of Geriatric Medicine and Gerontology, Centre for Health Services Research (CHESS), University of Warwick, UK.
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Whitnall MH, Inal CE, Jackson WE, Miner VL, Villa V, Seed TM. In vivo radioprotection by 5-androstenediol: stimulation of the innate immune system. Radiat Res 2001; 156:283-93. [PMID: 11500137 DOI: 10.1667/0033-7587(2001)156[0283:ivrbas]2.0.co;2] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
We showed previously that 5-androstenediol stimulates myelopoiesis, increases the numbers of circulating neutrophils and platelets, and enhances resistance to infection in gamma-irradiated mice. We have extended those studies to include monocytes, natural killer (NK) cells, eosinophils and basophils, and we have measured the activation marker CD11b using flow cytometry. Androstenediol (160 mg/kg) was administered subcutaneously to female B6D2F1 mice 24 h before whole-body gamma irradiation. Androstenediol treatments increased the blood levels of neutrophils, monocytes and NK cells in unirradiated animals; decreased the numbers of circulating eosinophils; and ameliorated radiation-induced decreases in neutrophils, monocytes, NK cells, erythrocytes and platelets. The androstenediol treatments had no significant effect on the numbers of circulating B cells or T cells. CD11b labeling intensity on monocytes was decreased slightly after androstenediol treatment. In contrast, radiation or androstenediol alone caused increases in CD11b labeling intensity on NK cells. Androstenediol and radiation combined caused a marked increase in NK cell CD11b. The results indicate that androstenediol increases the numbers of the three major cell types of the innate immune system (neutrophils, monocytes and NK cells), that androstenediol-induced changes in blood elements in irradiated animals persist for at least several weeks, and that there is a significant positive interaction between radiation and administration of androstenediol in the activation of NK cells.
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Affiliation(s)
- M H Whitnall
- Radiation Casualty Management Team, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA.
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Whitnall MH, Elliott TB, Landauer MR, Jackson WE, Wilhelmsen CL, Mckinney L, Kumar KS, Srinivasan V, Ledney GD, Seed TM. In vivo protection against gamma-irradiation with 5-androstenediol. Exp Biol Med (Maywood) 2001; 226:625-7. [PMID: 11444097 DOI: 10.1177/153537020222600707] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- M H Whitnall
- Radiation Casualty Management Team, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889-5603, USA
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Ciolino HP, Yeh GC. The steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression in vitro by a post-transcriptional mechanism. J Biol Chem 1999; 274:35186-90. [PMID: 10575002 DOI: 10.1074/jbc.274.49.35186] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The adrenal steroid hormone dehydroepiandrosterone (DHEA) is a potent inhibitor of mammary carcinogenesis induced by polycyclic aromatic hydrocarbons (PAH), though its mechanism is unclear. We examined the effect of DHEA on the expression of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1) in MCF-7 human breast epithelial carcinoma cells. DHEA inhibited the increase in CYP1A1 enzyme activity that occurs when MCF-7 cells are exposed to the PAH dimethylbenzanthracene (DMBA) or 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). However, DHEA did not directly inhibit enzyme activity as it had no effect when added to the cells after induction by DMBA or TCDD. We observed that the increase of CYP1A1 mRNA in MCF-7 cells caused by DMBA or TCDD was inhibited by DHEA in a concentration-dependent manner. However, DHEA did not inhibit CYP1A1 promoter-driven transcription, indicating that it did not affect the aryl hydrocarbon receptor, which regulates transcription of the CYP1A1 gene. Actinomycin D chase experiments showed that DHEA caused a time- and concentration-dependent decrease in CYP1A1 mRNA levels, indicating that DHEA inhibits CYP1A1 expression by decreasing CYP1A1 mRNA stability. These data demonstrate that DHEA inhibits PAH-induced CYP1A1 mRNA expression and enzyme activity in vitro by a post-transcriptional mechanism. This regulation of the expression of carcinogen-activating enzymes may be responsible for the chemopreventive activity of DHEA and may be one of its physiologic functions in vivo.
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Affiliation(s)
- H P Ciolino
- Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Division of Basic Sciences, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702-1201, USA.
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De Flora S, Bennicelli C, Bagnasco M. Rationale and mechanisms of cancer chemoprevention. Recent Results Cancer Res 1999; 151:29-44. [PMID: 10337717 DOI: 10.1007/978-3-642-59945-3_3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Chronic degenerative diseases, including cancer, have a multifactorial origin. An intricate network connects each disease with multiple risk factors and also with multiple protective factors. From the point of view of preventive medicine, this implies that removal of a single risk factor will have a beneficial impact on the epidemiology of several diseases. However, in contrast to the situation in infectious diseases, it will never be possible to eradicate any chronic degenerative disease in this way, because each of them is associated with other risk factors at the same time. Similarly, a single protective factor can decrease the risk of contracting different diseases, and the risk of developing a single disease can be attenuated by different protective factors, often in a coordinated fashion. It is thus evident that cancer can be prevented not only by avoiding exposure to recognized risk factors, but also, as a complementary approach referred to as chemoprevention, by favouring the intake of protective factors and by fortifying the physiological defences of the host organism. Chemoprevention can be applied in a primary prevention setting when it is addressed to healthy individuals with the goal of inhibiting occurrence of the disease. Conversely, it is applied in a secondary prevention setting when it is addressed to individuals affected by premalignant tumours, with the goal of reversing the carcinogenesis process. A rational use of chemopreventive agents is based not only on the assessment of their efficacy and safety but also on understanding of their mechanisms of action. A detailed classification is proposed, which covers a variety of mechanisms interfering with different phases of mutagenesis and carcinogenesis. However, this sequence of events does not fit in with a rigid scheme, and several mechanisms, such as inhibition of genotoxic effects, antioxidant activity and scavenging of free radicals, inhibition of cell proliferation, and signal transduction modulation are reiterated several times throughout evolution of these processes. Some of these mechanisms are also involved in advanced stages of tumour progression towards malignancy, invasion and metastasis, and can therefore conveniently be applied for the tertiary prevention of cancer. Most inhibitors work through multiple mechanisms, examples of which are given for 18 chemopreventive agents.
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Affiliation(s)
- S De Flora
- Institute of Hygiene and Preventive Medicine, University of Genoa, Italy
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Mayo JC, Sainz RM, Antolín I, Rodriguez C. Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage. Brain Res 1999; 818:221-7. [PMID: 10082807 DOI: 10.1016/s0006-8993(98)01262-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
6-Hydroxydopamine (6-OHDA) is a neurotoxin used in the induction of experimental Parkinson's disease in both animals and cultured neuronal cells. Biochemical and molecular approaches showed previously that low doses of 6-OHDA induced apoptosis in PC12 cells, while high doses of this neurotoxin induced necrosis. Melatonin has been shown to protect against the neuronal programmed cell death induced by 6-OHDA, although it was not able to prevent the massive necrotic cellular death occurring after the addition of high doses of the neurotoxin. In the present work, we demonstrate by ultrastructural analysis that although low doses of 6-OHDA induced apoptosis in PC12 cells, it also damaged the non-apoptotic cells, morphologically corresponding this damage to incipient and reversible necrotic lesions. When the doses of the neurotoxin increase, there are still apoptotic cells, although most of the cells show necrotic irreversible lesions. We also found that melatonin partially prevents the incipient necrotic lesions caused by low doses of 6-OHDA. The fact that melatonin was shown in previous work to prevent apoptosis caused by low doses of 6-OHDA, but not necrosis induced by high doses of the neurotoxin, seemed to indicate that this agent is only able to protect against apoptosis. However, our present results, melatonin preventing also the incipient necrotic neuronal lesions, suggest that this hormone may provide a general protection against cell death, suggesting that higher doses should be tried in order to prevent the necrotic cell death induced by high doses of the neurotoxin.
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Affiliation(s)
- J C Mayo
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Julian Claveria s/n, 33006, Oviedo, Spain
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Nippoldt TB, Nair KS. Is there a case for DHEA replacement? BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1998; 12:507-20. [PMID: 10332570 DOI: 10.1016/s0950-351x(98)80286-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
There are many hormonal changes that occur with ageing in humans, of which the most dramatic and intriguing change occurs for the adrenal androgenic steroid dehydroepiandosterone (DHEA). There are tantalizing epidemiological data demonstrating a significant association between the changes in circulating DHEA level and changes in the incidence of malignancy, atherosclerosis, Alzheimer's disease and other age-related changes. The pharmacological effects in animals such as rodents and rabbits have demonstrated many beneficial effects, for example increased immune function, the prevention of atherosclerosis, cancer, diabetes and obesity, and the improvement of memory. Clinical studies carried out in small groups of subjects have clearly demonstrated that the administration of DHEA to the elderly increases many hormone levels, including that of insulin-like growth factor-1, (free and total) testosterone, dihydrotestosterone, oestrone and oestradiol. It remains to be clearly defined whether these changes are clinically beneficial, and there is only insufficient information on the side-effects on long-term use. Results from short-term intervention studies in small groups of subjects have not demonstrated any convincing beneficial effects so far. A judgement on whether DHEA replacement has a place in preventing age-related disabilities could be determined only on the basis of results from studies of long-term DHEA replacement in elderly people.
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Affiliation(s)
- T B Nippoldt
- Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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Nephew KP, Sheeler CQ, Dudley MD, Gordon S, Nayfield SG, Khan SA. Studies of dehydroepiandrosterone (DHEA) with the human estrogen receptor in yeast. Mol Cell Endocrinol 1998; 143:133-42. [PMID: 9806358 DOI: 10.1016/s0303-7207(98)00128-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Dehydroepiandrosterone (DHEA) is a C19 adrenal steroid synthesized in the human adrenal cortex and serving as a biosynthetic precursor to testosterone and 17beta-estradiol. Despite the fact that it is one of the most abundant steroid hormones in circulation, the physiological role of DHEA in humans remains unclear. The action of DHEA itself, such as its interactions with receptors and nuclear transcription factors, is not well understood, and a specific DHEA receptor has yet to be identified. Although the activity of DHEA can be due to its metabolism into androgens and estrogens, DHEA has been shown to interact with the androgen receptor and the estrogen receptor (ER) in vitro. We demonstrate in this study that DHEA (3beta-Hydroxy-5alpha-androstan-17-one) inhibits 17beta-estradiol (E2) binding to its receptor in vivo in yeast. DHEA stimulates human ER dimerization in yeast, as determined by ER fusion protein interactions, GAL4 reconstitution and subsequent measurement of increased beta-galactosidase activity. DHEA causes an increase in estrogen response element-dependent beta-galactosidase activity, demonstrating that the ER dimer induced by DHEA is transcriptionally active, but at a concentration of DHEA about 1000 times greater than E2. Inclusion of the nuclear receptor co-activator RIP140 in the yeast enhances ER transactivation by DHEA or E2 in a ligand-dependent manner; moreover, only in the presence of RIP140 is DHEA able to stimulate beta-galactosidase activity to levels similar to those achieved by E2. Ligand-receptor interaction for other C19-steroids was also examined. While 5-androstene-3beta, 17beta-diol (ADIOL) displayed estrogenic activity in this system, 4-androstene-17-dione (androstenedione) and 4-androstene-17beta-ol,3-one (testosterone) did not. We have investigated whether DHEA can interact with the human ER in vivo. Our findings demonstrate a mechanism by which DHEA interacts directly with estrogen signaling systems; however, because DHEA is several orders of magnitude less potent than E2 in this system, we conclude that it essentially is not an estrogen agonist.
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Affiliation(s)
- K P Nephew
- Medical Sciences Program, Indiana University School of Medicine, Bloomington 47405-4401, USA.
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Abstract
OBJECTIVE To summarize the current information about dehydroepiandrosterone (DHEA), a steroid hormone produced in the adrenal cortex. METHODS The biochemical and physiologic features of DHEA and its purported effects on overall age-related decline and on various disorders are reviewed. In addition, the potential side effects from administration of DHEA are discussed. RESULTS During the normal life cycle, levels of DHEA fluctuate, beginning with production of large quantities in the fetus, stopping at birth, resuming during ages 5 to 7 years, and increasing throughout puberty to maximal production in the 20s. Thereafter, DHEA levels progressively decline. This age-related decline in physiologic levels of DHEA has prompted speculation about a relationship between relative "DHEA deficiency" in older age and diseases of aging as well as the possibility of deriving benefits from administration of DHEA. Certain studies in animals (primarily rodents) have suggested anticancer effects of DHEA in pharmacologic doses and improvement in metabolism. In various studies in animals and humans, discrepant results have been found in the assessment of the association between DHEA levels and coronary artery disease. Likewise, the clinical significance of changes in immune function with DHEA treatment is unknown. Because DHEA is classified as a "nutritional supplement," it is not subjected to government regulation, and a potential exists for inaccurate dosage and impurities. CONCLUSION Studies have shown that DHEA influences multiple systems and disease processes in animals and humans; some of these effects could be considered beneficial and others detrimental. To date, no long-term health benefits from DHEA in "replacement" doses have been demonstrated.
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Affiliation(s)
- T B Nippoldt
- Division of Endocrinology, Metabolism, Nutrition, and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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Scheven BA, Milne JS. Dehydroepiandrosterone (DHEA) and DHEA-S interact with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to stimulate human osteoblastic cell differentiation. Life Sci 1998; 62:59-68. [PMID: 9444968 DOI: 10.1016/s0024-3205(97)01038-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
DHEA, an adrenocortical steroid, and its sulfate derivative (DHEA-S), have been implicated in many biological functions, including the regulation of bone mass. In this study, we examined whether DHEA/DHEA-S are capable of directly affecting bone cell proliferation and differentiation, and compared this with the effects of, and interaction with, the established bone cell modulating steroid, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Two in vitro models of human osteoblastic cells were used, viz. MG63 osteosarcoma cell line and normal primary osteoblast-like cells (HOB). Our results show that DHEA and DHEA-S failed on their own to exert direct, independent significant effects on the growth and differentiation of human osteoblastic cells, but treating the cells in conjunction with 1,25(OH)2D3 resulted in enhancement of specific A1P activity. Moreover, 1,25(OH)2D3-induced osteocalcin production was potentiated by the adrenal steroids in both cell models. DHEA-S proved in general to be more potent than DHEA. In conclusion, this study shows that the effects of DHEA/DHEA-S on osteoblastic cell growth and differentiation are likely to be mediated via an effect on 1,25(OH)2D3-induced changes in bone cells, suggesting a distinctive role for these steroids in the regulation of bone metabolism.
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Affiliation(s)
- B A Scheven
- Rowett Research Institute, Skeletal Research Unit, Bucksburn, Scotland, UK
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Abstract
Ageing is associated with changes in the secretion of adrenal cortical steroids. In the elderly, cortisol secretion increases after stimulation, while the secretion of dehydroepiandrosterone (DHEA) decreases. Each of these hormones influences the age-related processes of energy metabolism, fat depot distribution, immune function and neurodegeneration. In animals the effects of adrenal steroids are dramatic and easily measured. In humans the effects are more subtle. This review summarizes these actions and emphasizes the differences of dosages used in various experimental designs. It is concluded that adrenal hormones may play a significant role in human ageing, but research is hindered because the molecular pathways of DHEA action are not known.
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Affiliation(s)
- F Svec
- Section of Endocrinology, Louisiana State University Medical School, New Orleans 70112, USA
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Connelly TJ, Kowalcyk AP. Another case of spontaneous regression of Merkel cell (neuroendocrine) carcinoma. Dermatol Surg 1997; 23:588-90. [PMID: 9236880 DOI: 10.1111/j.1524-4725.1997.tb00695.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Merkel cell (neuroendocrine) carcinoma (MCC) is a very aggressive primary cutaneous neoplasm most often occurring on the head and neck of the elderly. Spontaneous regression of MCC was first described in this journal in 1986. Since then, other such cases have been reported. This case represents the sixth case of spontaneous regression of MCC. OBJECTIVE To describe to clinical course in a patient with MCC who underwent spontaneous regression of metastatic disease. METHODS Clinical records including detailed history and frequent follow-up examination made this observation possible. RESULTS Complete clinically evident regression of metastatic MCC was observed in this case. However, the patient received no treatment known to be effective for MCC. CONCLUSIONS Spontaneous regression of MCC has been documented. The reason for regression is unknown. Further study of these rare cases may in the future provide more answers than questions.
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Affiliation(s)
- T J Connelly
- Connelly Skin Cancer Surgery Center, Stuarl, FL 34994, USA
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Kelloff GJ, Boone CW, Crowell JA, Steele VE, Lubet RA, Doody LA, Malone WF, Hawk ET, Sigman CC. New agents for cancer chemoprevention. JOURNAL OF CELLULAR BIOCHEMISTRY. SUPPLEMENT 1996; 26:1-28. [PMID: 9154166 DOI: 10.1002/jcb.240630703] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids [e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid], calcium, Beta carotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylornithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs. Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.
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Affiliation(s)
- G J Kelloff
- Chemoprevention Branch, National Cancer Institute (NCI), Bethesda, MD 20892, USA
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