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Zarrella S, Miranda MR, Covelli V, Restivo I, Novi S, Pepe G, Tesoriere L, Rodriquez M, Bertamino A, Campiglia P, Tecce MF, Vestuto V. Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer. Metabolites 2025; 15:221. [PMID: 40278350 PMCID: PMC12029571 DOI: 10.3390/metabo15040221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 04/26/2025] Open
Abstract
Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.
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Affiliation(s)
- Salvatore Zarrella
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Maria Rosaria Miranda
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Verdiana Covelli
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Ignazio Restivo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Sara Novi
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Giacomo Pepe
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
- NBFC, National Biodiversity Future Center, 90133 Palermo, Italy
| | - Luisa Tesoriere
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Via Archirafi 28, 90123 Palermo, Italy; (I.R.); (L.T.)
| | - Manuela Rodriquez
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Napoli, Italy; (V.C.); (M.R.)
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
| | - Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy; (S.Z.); (M.R.M.); (S.N.); (G.P.); (A.B.); (P.C.); (M.F.T.)
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Siatka T, Mát'uš M, Moravcová M, Harčárová P, Lomozová Z, Matoušová K, Suwanvecho C, Krčmová LK, Mladěnka P. Biological, dietetic and pharmacological properties of vitamin B 9. NPJ Sci Food 2025; 9:30. [PMID: 40075081 PMCID: PMC11904035 DOI: 10.1038/s41538-025-00396-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
Humans must obtain vitamin B9 (folate) from plant-based diet. The sources as well as the effect of food processing are discussed in detail. Industrial production, fortification and biofortification, kinetics, and physiological role in humans are described. As folate deficiency leads to several pathological states, current opinions toward prevention through fortification are discussed. Claimed risks of increased folate intake are mentioned as well as analytical ways for measurement of folate.
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Affiliation(s)
- Tomáš Siatka
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Marek Mát'uš
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University Bratislava, Odbojárov 10, 83232, Bratislava, Slovak Republic
| | - Monika Moravcová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Patrícia Harčárová
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Zuzana Lomozová
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05, Hradec Králové, Czech Republic
| | - Chaweewan Suwanvecho
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 03, Hradec Králové, Czech Republic.
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Sallam M, Nguyen NT, Sainsbury F, Kimizuka N, Muyldermans S, Benešová-Schäfer M. PSMA-targeted radiotheranostics in modern nuclear medicine: then, now, and what of the future? Theranostics 2024; 14:3043-3079. [PMID: 38855174 PMCID: PMC11155394 DOI: 10.7150/thno.92612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/04/2024] [Indexed: 06/11/2024] Open
Abstract
In 1853, the perception of prostate cancer (PCa) as a rare ailment prevailed, was described by the eminent Londoner surgeon John Adams. Rapidly forward to 2018, the landscape dramatically altered. Currently, men face a one-in-nine lifetime risk of PCa, accentuated by improved diagnostic methods and an ageing population. With more than three million men in the United States alone grappling with this disease, the overall risk of succumbing to stands at one in 39. The intricate clinical and biological diversity of PCa poses serious challenges in terms of imaging, ongoing monitoring, and disease management. In the field of theranostics, diagnostic and therapeutic approaches that harmoniously merge targeted imaging with treatments are integrated. A pivotal player in this arena is radiotheranostics, employing radionuclides for both imaging and therapy, with prostate-specific membrane antigen (PSMA) at the forefront. Clinical milestones have been reached, including FDA- and/or EMA-approved PSMA-targeted radiodiagnostic agents, such as [18F]DCFPyL (PYLARIFY®, Lantheus Holdings), [18F]rhPSMA-7.3 (POSLUMA®, Blue Earth Diagnostics) and [68Ga]Ga-PSMA-11 (Locametz®, Novartis/ ILLUCCIX®, Telix Pharmaceuticals), as well as PSMA-targeted radiotherapeutic agents, such as [177Lu]Lu-PSMA-617 (Pluvicto®, Novartis). Concurrently, ligand-drug and immune therapies designed to target PSMA are being advanced through rigorous preclinical research and clinical trials. This review delves into the annals of PSMA-targeted radiotheranostics, exploring its historical evolution as a signature molecule in PCa management. We scrutinise its clinical ramifications, acknowledge its limitations, and peer into the avenues that need further exploration. In the crucible of scientific inquiry, we aim to illuminate the path toward a future where the enigma of PCa is deciphered and where its menace is met with precise and effective countermeasures. In the following sections, we discuss the intriguing terrain of PCa radiotheranostics through the lens of PSMA, with the fervent hope of advancing our understanding and enhancing clinical practice.
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Affiliation(s)
- Mohamed Sallam
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- School of Environment and Science (ESC), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Griffith Institute for Drug Discovery (GRIDD), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Nam-Trung Nguyen
- Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Frank Sainsbury
- School of Environment and Science (ESC), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
- Griffith Institute for Drug Discovery (GRIDD), Griffith University, Nathan Campus, Nathan, QLD 4111, Australia
| | - Nobuo Kimizuka
- Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan
- Center for Molecular Systems (CMS), Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan
- Research Center for Negative Emissions Technologies (K-NETs), Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan
| | - Serge Muyldermans
- Laboratory of Cellular and Molecular Immunology (CMIM), Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Martina Benešová-Schäfer
- Research Group Molecular Biology of Systemic Radiotherapy, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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Yarmolinsky J, Robinson JW, Mariosa D, Karhunen V, Huang J, Dimou N, Murphy N, Burrows K, Bouras E, Smith-Byrne K, Lewis SJ, Galesloot TE, Kiemeney LA, Vermeulen S, Martin P, Albanes D, Hou L, Newcomb PA, White E, Wolk A, Wu AH, Le Marchand L, Phipps AI, Buchanan DD, Zhao SS, Gill D, Chanock SJ, Purdue MP, Davey Smith G, Brennan P, Herzig KH, Järvelin MR, Amos CI, Hung RJ, Dehghan A, Johansson M, Gunter MJ, Tsilidis KK, Martin RM. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis. EBioMedicine 2024; 100:104991. [PMID: 38301482 PMCID: PMC10844944 DOI: 10.1016/j.ebiom.2024.104991] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10-8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P-value ("q-value") <0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q-value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH4) >70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
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Affiliation(s)
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK.
| | - Jamie W Robinson
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Daniela Mariosa
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Ville Karhunen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland; Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
| | - Jian Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Karl Smith-Byrne
- The Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | | | | | - Sita Vermeulen
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Paul Martin
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, UK
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lifang Hou
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna H Wu
- University of Southern California, Preventative Medicine, Los Angeles, CA, USA
| | - Loïc Le Marchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomic Group, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia; Genetic Medicine and Family Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Sizheng Steven Zhao
- Centre for Epidemiology Versus Arthritis, Faculty of Biological Medicine and Health, University of Manchester, Manchester, UK
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Mark P Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Paul Brennan
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Karl-Heinz Herzig
- Institute of Biomedicine, Medical Research Center and Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Marjo-Riitta Järvelin
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France; Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
| | - Chris I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Abbas Dehghan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Dementia Research Institute, Imperial College London, London, UK
| | - Mattias Johansson
- Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Kostas K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Richard M Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; University Hospitals Bristol and Weston NHS Foundation Trust, National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
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Fouillet J, Donzé C, Deshayes E, Santoro L, Rubira L, Fersing C. "One Method to Label Them All": A Single Fully Automated Protocol for GMP-Compliant 68Ga Radiolabeling of PSMA-11, Transposable to PSMA-I&T and PSMA-617. Curr Radiopharm 2024; 17:285-301. [PMID: 38424422 PMCID: PMC11348474 DOI: 10.2174/0118744710293461240219111852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Prostate-specific membrane antigen (PSMA) is an ideal target for molecular imaging and targeted radionuclide therapy in prostate cancer. Consequently, various PSMA ligands were developed. Some of these molecules are functionalized with a chelator that can host radiometals, such as 68Ga for PET imaging. The 68Ga radiolabeling step benefits from process automation, making it more robust and reducing radiation exposure. OBJECTIVE To design a single automated radiolabeling protocol for the GMP-compliant preparation of [68Ga]Ga-PSMA-11, transposable to the production of [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-I&T. METHODS A GAIA® synthesis module and a GALLIAD® generator were used. Radio-TLC and radio-HPLC methods were validated for radiochemical purity (RCP) determination. Three [68Ga]Ga-PSMA-11 validation batches were produced and thoroughly tested for appearance and pH, radionuclide identity and purity, RCP, stability, residual solvent and sterility. Minimal modifications were made to the reagents and disposables for optimal application to other PSMA ligands. RESULTS [68Ga]Ga-PSMA-11 for clinical application was produced in 27 min. The 3 validation batches met the quality criteria expected by the European Pharmacopoeia to allow routine production. For optimal transposition to PSMA-617, the solid phase extraction cartridge was changed to improve purification of the radiolabeled product. For application to PSMA-I&T, the buffer solution initially used was replaced by HEPES 2.7 M to achieve good radiochemical yields. Residual HEPES content was checked in the final product and was below the Ph. Eur. threshold. CONCLUSION A single automated radiolabeling method on the GAIA® module was developed and implemented for 68Ga radiolabeling of 3 PSMA ligands, with slight adjustments for each molecule.
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Affiliation(s)
- Juliette Fouillet
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
| | - Charlotte Donzé
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
| | - Emmanuel Deshayes
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194,University of Montpellier, Montpellier, France
| | - Lore Santoro
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194,University of Montpellier, Montpellier, France
| | - Léa Rubira
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
| | - Cyril Fersing
- Nuclear Medicine Department, Institut Régional du Cancer de Montpellier (ICM), University of Montpellier , Montpellier, France
- IBMM, University of Montpellier, CNRS, ENSCM, Montpellier, France
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Thabet RH, Alessa REM, Al-Smadi ZKK, Alshatnawi BSG, Amayreh BMI, Al-Dwaaghreh RBA, Salah SKA. Folic acid: friend or foe in cancer therapy. J Int Med Res 2024; 52:3000605231223064. [PMID: 38229460 PMCID: PMC10935767 DOI: 10.1177/03000605231223064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 12/11/2023] [Indexed: 01/18/2024] Open
Abstract
Folic acid plays a crucial role in diverse biological processes, notably cell maturation and proliferation. Here, we performed a literature review using articles listed in electronic databases, such as PubMed, Scopus, MEDLINE, and Google Scholar. In this review article, we describe contradictory data regarding the role of folic acid in cancer development and progression. While some studies have confirmed its beneficial effects in diminishing the risk of various cancers, others have reported a potential carcinogenic effect. The current narrative review elucidates these conflicting data by highlighting the possible molecular mechanisms explaining each point of view. Further multicenter molecular and genetic studies, in addition to human randomized clinical trials, are necessary to provide a more comprehensive understanding of the relationship between folic acid and cancer.
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Affiliation(s)
- Romany H. Thabet
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Department of Basic Medical Sciences, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba, Jordan
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Fardous AM, Heydari AR. Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients 2023; 15:4699. [PMID: 37960352 PMCID: PMC10648405 DOI: 10.3390/nu15214699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/26/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.
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Affiliation(s)
- Ali M. Fardous
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
| | - Ahmad R. Heydari
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
- Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
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8
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Goldstein MR, Mascitelli L. Prostate-Specific Membrane Antigen (PSMA), Androgen Modulation, Folic Acid, and High-Grade Prostate Cancer: An Intriguing Nexus Needing Attention. Med Hypotheses 2023. [DOI: 10.1016/j.mehy.2023.111050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
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9
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Hawkey NM, Sartor AO, Morris MJ, Armstrong AJ. Prostate-specific membrane antigen-targeted theranostics: past, present, and future approaches. CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY : H&O 2022; 20:227-238. [PMID: 35389387 PMCID: PMC9423035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Although prostate cancer is the type of cancer most commonly survived by men in the United States, it remains the second most common cause of death from cancer, largely owing to metastatic disease. Patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed on standard-of-care therapies have few options and a poor prognosis. Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein that is commonly expressed in prostate cancer. Expression is limited on extra-prostatic tissues other than the salivary glands, lacrimal glands, duodenal epithelium, Kupffer cells, and renal tubules. PSMA-directed theranostics has emerged to exploit the specificity of PSMA for prostate cancer cells and has demonstrated promising results in the clinic. Radionuclides linked to PSMA inhibitors/binders have resulted in US Food and Drug Administration (FDA) approval of 2 radiodiagnostics for PSMA-directed positron emission tomography/computed tomography. In addition, these radionuclides have led to the development of lutetium Lu 177PSMA-617 therapy, which is currently under priority FDA review. Multiple novel PSMA-targeted modalities have been developed and are currently under clinical investigation, including ligand-drug and cellular immune therapies. In this review, we discuss the development of PSMA-directed theranostics, along with its clinical implications, limitations, and future directions.
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Affiliation(s)
- Nathan M. Hawkey
- Department of Medicine, Duke University School of Medicine, Division of Medical Oncology, Durham, North Carolina
| | - Alton O. Sartor
- Tulane Cancer Center, Division of Genitourinary Oncology, New Orleans, Louisiana
| | - Michael J. Morris
- Memorial Sloan Kettering Cancer Center, Genitourinary Oncology Service, New York, New York
| | - Andrew J. Armstrong
- Department of Medicine, Duke University School of Medicine, Division of Medical Oncology, Durham, North Carolina
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
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10
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Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles. Biomolecules 2022; 12:biom12020197. [PMID: 35204698 PMCID: PMC8961567 DOI: 10.3390/biom12020197] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.
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11
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Gasmi A, Bjørklund G, Noor S, Semenova Y, Dosa A, Pen JJ, Menzel A, Piscopo S, Wirth N, Costea DO. Nutritional and surgical aspects in prostate disorders. Crit Rev Food Sci Nutr 2022:1-17. [PMID: 35021909 DOI: 10.1080/10408398.2021.2013158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Prostate disorders are commonplace in medicine, especially in older men, with prostatitis, benign prostatic hyperplasia, and prostate cancer being the most abundant pathologies. The complexity of this organ, however, turns treatment into a challenge. In this review, we aim to provide insight into the efficacy of alternative treatments, which are not normally used in conventional medicine, with a particular focus on nutrients. In order to understand why and how nutrition can be beneficial in diseases of the prostate, we give an overview of the known characteristics and features of this organ. Then, we provide a summary of the most prevalent prostate illnesses. Finally, we propose nutrition-based treatment in each of these prostate problems, based on in-depth research concerning its effects in this context, with an emphasis on surgery. Overall, we plead for an upgrade of this form of alternative treatment to a fully recognized mode of therapy for the prostate.
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Affiliation(s)
- Amin Gasmi
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France.,Laboratoire Interuniversitaire de Biologie de la Motricité, Université Lyon 1, Villeurbanne, France
| | - Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
| | - Sadaf Noor
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University Multan, Multan, Pakistan
| | - Yuliya Semenova
- Department of Neurology, Ophthalmology, ENT, Semey Medical University, Semey, Kazakhstan.,CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, Semey, Kazakhstan
| | - Alexandru Dosa
- Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
| | - Joeri J Pen
- Diabetes Clinic, Department of Internal Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Department of Nutrition, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | | | - Salva Piscopo
- Société Francophone de Nutrithérapie et de Nutrigénétique Appliquée, Villeurbanne, France
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12
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Puga AM, Ruperto M, Samaniego-Vaesken MDL, Montero-Bravo A, Partearroyo T, Varela-Moreiras G. Effects of Supplementation with Folic Acid and Its Combinations with Other Nutrients on Cognitive Impairment and Alzheimer's Disease: A Narrative Review. Nutrients 2021; 13:2966. [PMID: 34578844 PMCID: PMC8470370 DOI: 10.3390/nu13092966] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/04/2021] [Accepted: 08/20/2021] [Indexed: 01/24/2023] Open
Abstract
Cognitive impairment and Alzheimer's Disease, among other cognitive dysfunctions, has been recognized as a major public health problem. Folic acid is a well-known essential nutrient whose deficiency has been linked to neurocognitive dysfunctions, owing to hyperhomocysteinemia, an independent risk factor for cardio- and cerebrovascular diseases, including cognitive impairment, Alzheimer's Disease, and vascular dementia. However, to date, there is certain controversy about the efficacy of vitamin supplementation in patients with these pathologies. Therefore, we have reviewed the available dietary intervention studies based on folic acid, either alone or in combination with different vitamins or nutrients into the progression of Alzheimer's Disease and Cognitive impairment, highlighting the cognition and biochemical markers employed for the evaluation of the disease progression. Undeniably, the compiled information supports the potential benefits of vitamin supplementation in these pathologies, especially relevant to the aging process and quality of life, although more research is urgently needed to confirm these positive findings.
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Affiliation(s)
- Ana M. Puga
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
| | - Mar Ruperto
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
| | - Mª de Lourdes Samaniego-Vaesken
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
| | - Ana Montero-Bravo
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
| | - Teresa Partearroyo
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
| | - Gregorio Varela-Moreiras
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Alcorcón, 28925 Madrid, Spain; (A.M.P.); (M.R.); (M.d.L.S.-V.); (A.M.-B.); (T.P.)
- Grupo USP-CEU de Excelencia “Nutrición para la vida (Nutrition for Life)”, ref: E02/0720, Alcorcón, 28925 Madrid, Spain
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13
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Evolving Castration Resistance and Prostate Specific Membrane Antigen Expression: Implications for Patient Management. Cancers (Basel) 2021; 13:cancers13143556. [PMID: 34298770 PMCID: PMC8307676 DOI: 10.3390/cancers13143556] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease, despite multiple novel treatment options. The role of prostate-specific membrane antigen (PSMA) in the process of mCRPC development has long been underestimated. During the last years, a new understanding of the underlying molecular mechanisms of rising PSMA expression and its association with disease progression has emerged. Accurate understanding of these complex interactions is indispensable for a precise diagnostic process and ultimately successful treatment of advanced prostate cancer. The combination of different novel therapeutics such as androgen deprivation agents, 177LU-PSMA radioligand therapy and PARP inhibitors promises a new kind of efficacy. In this review, we summarize the current knowledge about the most relevant molecular mechanisms around PSMA in mCRPC development and how they can be implemented in mCRPC management.
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14
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Coleman MF, O’Flanagan CH, Pfeil AJ, Chen X, Pearce JB, Sumner S, Krupenko SA, Hursting SD. Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction. Nutrients 2021; 13:nu13051637. [PMID: 34068120 PMCID: PMC8152779 DOI: 10.3390/nu13051637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.
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Affiliation(s)
- Michael F. Coleman
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
| | - Ciara H. O’Flanagan
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
| | - Alexander J. Pfeil
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
| | - Xuewen Chen
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
| | - Jane B. Pearce
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
| | - Susan Sumner
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081, USA
| | - Sergey A. Krupenko
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081, USA
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA; (M.F.C.); (C.H.O.); (A.J.P.); (X.C.); (J.B.P.); (S.S.); (S.A.K.)
- Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
- Correspondence:
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15
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Liss MA, Ashcraft K, Satsangi A, Bacich D. Rise in serum folate after androgen deprivation associated with worse prostate cancer-specific survival. Urol Oncol 2020; 38:682.e21-682.e27. [PMID: 32444177 PMCID: PMC10866043 DOI: 10.1016/j.urolonc.2020.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 02/09/2020] [Accepted: 04/06/2020] [Indexed: 01/16/2023]
Abstract
INTRODUCTION High folate has an association with advanced prostate cancer and levels of testosterone. Herein, we perform a translational study to investigate the inverse response of serum folate in prostate cancer patients initiating androgen deprivation therapy (ADT) and a mirrored animal model. METHODS A retrospective study was performed using the South Texas Veterans Healthcare System to identify patients with prostate cancer on ADT. We documented testosterone and folate levels before and after ADT initiation (defined by a reduction in testosterone by 50 ng/ml) as compared to those already on ADT (maintenance). Our primary outcome was overall mortality with secondary outcome of prostate cancer-specific mortality. In parallel, we tested castration of C57BL/6J mice on folate-defined diet to determine if folate levels change with response to androgen deprivation. Students' t test on continuous variables and Chi-squared test on dichotomous variables was performed along with Kaplan-Meier for time to event analysis. RESULTS We identified 56 men with prostate cancer undergoing androgen deprivation in which folate levels had been determined. 15 out of 16 (94%) men initiating ADT had increases in their folate, which is substantially more than 67% in maintenance group (P = 0.04). We identified more rapid time to death from prostate cancer if folate levels increased to levels >200 ng/ml above their baseline (P = 0.03). Mice models demonstrated a significant rise in serum red blood cell folate after mice were castrated (P = 0.03) by an average of 1.5x over pre-castrated baseline level. By contrast, sham-castrated mice showed no increase in serum folate levels over baseline. CONCLUSION Our study suggests that men with substantial rises in folate after initiating ADT may be associated with worse prostate cancer-specific and overall survival. Our translational experiments in mice confirmed correlation between rising in folate levels post-castration. Given this study, further investigation is warranted on the role of dietary folate consumption during initiation of ADT and progression to castrate-resistant prostate cancer.
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Affiliation(s)
- Michael A Liss
- University of Texas Health San Antonio, Department of Urology, San Antonio, TX.
| | - Keith Ashcraft
- University of Texas Health San Antonio, Department of Urology, San Antonio, TX
| | - Arpan Satsangi
- University of Texas Health San Antonio, Department of Urology, San Antonio, TX
| | - Dean Bacich
- University of Texas Health San Antonio, Department of Urology, San Antonio, TX
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16
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Yarmolinsky J, Wade KH, Richmond RC, Langdon RJ, Bull CJ, Tilling KM, Relton CL, Lewis SJ, Davey Smith G, Martin RM. Causal Inference in Cancer Epidemiology: What Is the Role of Mendelian Randomization? Cancer Epidemiol Biomarkers Prev 2018; 27:995-1010. [PMID: 29941659 PMCID: PMC6522350 DOI: 10.1158/1055-9965.epi-17-1177] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/15/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023] Open
Abstract
Observational epidemiologic studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) uses genetic variants to proxy modifiable exposures to generate more reliable estimates of the causal effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within cardio-metabolic epidemiology, but also holds much promise for identifying possible interventions for cancer prevention and treatment. However, some methodologic challenges in the implementation of MR are particularly pertinent when applying this method to cancer etiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies. In this review, we provide an overview of the key principles and assumptions of MR, focusing on applications of this method to the study of cancer etiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared with conventional epidemiological studies. Finally, limitations of MR and recent methodologic developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 995-1010. ©2018 AACR.
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Affiliation(s)
- James Yarmolinsky
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Kaitlin H Wade
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Rebecca C Richmond
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Ryan J Langdon
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Caroline J Bull
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Kate M Tilling
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Caroline L Relton
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Sarah J Lewis
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Richard M Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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17
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Awwad HM, Ohlmann CH, Stoeckle M, Geisel J, Obeid R. Serum concentrations of folate vitamers in patients with a newly diagnosed prostate cancer or hyperplasia. Clin Biochem 2018; 56:41-46. [PMID: 29673813 DOI: 10.1016/j.clinbiochem.2018.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/09/2018] [Accepted: 04/15/2018] [Indexed: 12/01/2022]
Abstract
BACKGROUND Folate is required for synthesis of methyl groups and DNA in growing cells. The association between folate and prostate cancer (PCa) is not conclusive. METHODS We investigated concentrations of folate vitamers, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) in blood of men with PCa (n = 129) or benign prostatic hyperplasia (BPH) (n = 73) who were recruited just after the first diagnosis. RESULTS In younger subjects <65 years, concentrations of (6S)-5-CH3-H4folate (15.3 vs. 17.7 nmol/L) or total folate (UPLC-MS/MS) (18.7 vs. 23.0 nmol/L) did not differ between men with BPH and those with PCa, while SAM was higher in the controls (128 vs. 116 nmol/L). Younger patients with low- and high grade cancer did not differ in (6S)-5-CH3-H4folate (17.8 vs. 17.3 nmol/L) or total folate (UPLC-MS/MS) (22.9 vs. 23.3 nmol/L), but SAM was lower in patients with low grade PCa (111 vs. 126 nmol/L). In the older group ≥65 years, (6S)-5-CH3-H4folate (18.4 vs. 18.2 nmol/L) and total folate (UPLC-MS/MS) (22.5 vs. 22.1 nmol/L) did not differ between BPH and PCa. Older patients with advanced tumors had lower (6S)-5-CH3-H4folate compared with those with low grade tumor (12.8 vs. 20.0 nmol/L: p = 0.013). Plasma SAM was not different between older patients and controls and was not related to PCa grade. CONCLUSIONS Lowered serum methyl folate measured at the time of diagnosis in older patients with advanced PCa, and lowered plasma SAM in younger patients with low grade PCa suggest differential folate metabolism that may have mechanistic, prognostic or predictive values.
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Affiliation(s)
- Hussain Mohamad Awwad
- Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, D-66421 Homburg/Saar, Germany.
| | | | - Michael Stoeckle
- Department of Urology, Saarland University Hospital, D-66421 Homburg/Saar, Germany
| | - Juergen Geisel
- Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, D-66421 Homburg/Saar, Germany
| | - Rima Obeid
- Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, D-66421 Homburg/Saar, Germany.
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O'Keefe DS, Bacich DJ, Huang SS, Heston WDW. A Perspective on the Evolving Story of PSMA Biology, PSMA-Based Imaging, and Endoradiotherapeutic Strategies. J Nucl Med 2018; 59:1007-1013. [PMID: 29674422 DOI: 10.2967/jnumed.117.203877] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 04/03/2018] [Indexed: 12/16/2022] Open
Abstract
In this review, we cover the evolution of knowledge on the biology of prostate-specific membrane antigen (PSMA) and its translation to therapy. The usual key to discovery is a realistic model for experimentation and for testing a hypothesis. A realistic model is especially needed in the case of the human prostate, which differs significantly from the prostate of species often used as research models. We will emphasize the genetic characterization of PSMA, the nature of the PSMA protein, and its role as a carboxypeptidase, with differing important substrates and products in different tissues. We give special prominence to the importance of PSMA as a target for imaging and therapy in prostate cancer and its underdeveloped role for imaging and targeting the neovasculature of tumors other than prostate cancer. Lastly, we bring attention to its importance in other nonprostatic tissues.
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Affiliation(s)
- Denise S O'Keefe
- Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Dean J Bacich
- Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Steve S Huang
- Imaging Institute and Cancer Biology Department, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Warren D W Heston
- Department of Cancer Biology, Lerner Research Institute and Glickman Urologic Institute, Cleveland Clinic, Cleveland, Ohio
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Geiger H. Balance your folate or the yin and yang of folate in hematopoiesis. Haematologica 2017; 102:1969-1970. [PMID: 29192129 DOI: 10.3324/haematol.2017.179838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Hartmut Geiger
- Institute of Molecular Medicine and Aging Research Center, University of Ulm, Germany and Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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20
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Lin PH, Aronson W, Freedland SJ. An update of research evidence on nutrition and prostate cancer. Urol Oncol 2017; 37:387-401. [PMID: 29103966 DOI: 10.1016/j.urolonc.2017.10.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 09/15/2017] [Accepted: 10/06/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND Prostate cancer (PCa) remains a leading cause of mortality in US and other countries. Preclinical and clinical studies have examined the role of nutrition and dietary intake on the incidence and progression of PCa with mixed results. OBJECTIVE The objective of this chapter is to provide an update of recent published literature and highlight progress in the field. MAIN FINDINGS Low carbohydrate intake, soy protein, ω3 fat, green teas, tomatoes and tomato products and the herbal mixture-zyflamend showed promise in reducing PCa risk or progression. On the contrary, a higher animal fat intake and a higher β-carotene status may increase risk. A "U" shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Conclusion Despite the inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa remains promising. Maintaining a healthy body weight and following a healthy dietary pattern including antioxidant rich fruits and vegetables, reduced animal fat and refined carbohydrates, should be encouraged. CONCLUSION Despite the inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa remains promising. Maintaining a healthy body weight and following a healthy dietary pattern including antioxidant rich fruits and vegetables, reduced animal fat and refined carbohydrates, should be encouraged.
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Affiliation(s)
- Pao-Hwa Lin
- Department of Medicine, Duke University Medical Center, Durham, NC.
| | - William Aronson
- Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; Department of Urology, UCLA School of Medicine, Los Angeles, CA
| | - Stephen J Freedland
- Department of Surgery, Center for Integrated Research on Cancer and Lifestyle, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; Section of Urology, Department of Surgery, Durham Veterans Affairs Medical Center, Durham, NC
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21
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Liew SC. Folic acid and diseases - supplement it or not? Rev Assoc Med Bras (1992) 2016; 62:90-100. [PMID: 27008500 DOI: 10.1590/1806-9282.62.01.90] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 05/31/2015] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION folic acid is a water soluble vitamin, which is synthetically-produced and found in fortified foods and supplements. Folate is found naturally in plants, such as the dark green leafy vegetables. Folate is not synthesized de novo by humans, therefore the daily requirements are met from the dietary intake of folic acid supplements or food rich in this vitamin. Folate deficiency could lead to numerous common health problems. Hyperhomocysteinemia and the possibility of malignancy developments are the long term consequences of this deficit albeit contradictory findings on these claims. METHODS the articles included in this review focused on recent updated evidence-based reports and meta-analyses on the associations of the serum folate/folic acid and the various diseases found globally. RESULTS the benefit of folic acid supplementation in the pre-conception period for the prevention of neural tube defects (NTDs) was well established and it was suggested that counseling sessions should be given to women with previous pregnancies affected by NTDs. However, supplementation of folic acid and its medicinal effects in the treatment of other diseases were contradictory and unclear. CONCLUSION more detailed investigations into the health benefits of folic acid are needed before it could be recommended for supplementation, treatment or prevention of some of the diseases discussed in this review.
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Affiliation(s)
- Siaw-Cheok Liew
- Clinical Skills and Simulation Centre, International Medical University, Kuala Lumpur, Malaysia
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22
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Cipolleschi MG, Marzi I, Rovida E, Olivotto M, Dello Sbarba P. Low-dose methotrexate enhances cycling of highly anaplastic cancer cells. Cell Cycle 2016; 16:280-285. [PMID: 27841718 PMCID: PMC5323031 DOI: 10.1080/15384101.2016.1252883] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
We previously showed that cellular RedOx state governs the G1-S transition of AH130 hepatoma, a tumor spontaneously reprogrammed to the embryonic stem cell stage. This transition is impaired when the mithocondrial electron transport system is blocked by specific inhibitors (antimycin A) or the respiratory chain is saturated by adding to the cells high concentrations of pyruvate. The antimycin A or pyruvate block is removed by the addition of adequate concentrations of folate (F). This suggests that the G1-S transition of AH130 cells depends on a respiration-linked step of DNA synthesis related to folate metabolism. In the study reported here, we characterized the effects of methotrexate (MTX), an inhibitor of dihydofolate-reductase, on the G1-S transition of hepatoma cells, in the absence or the presence of exogenously added F, dihydrofolate (FH2) or tetrahydrofolate (FH4). MTX, at 1 μM or higher concentrations, inhibited G1-S transition. This inhibition was completely removed by exogenous folates. Surprisingly, 10 nM MTX stimulated G1-S transition. The addition of F, but not FH2 or FH4, significantly increased this effect. Furthermore, 10 nM MTX removed the block of the G1-S transition operated by antimycin A or pyruvate, an effect which was enhanced in the presence of F. Finally, the stimulatory effect of 10 nM MTX was inhibited in the presence of serine. Our findings indicated that, under certain conditions, MTX may stimulate, rather than inhibiting, the cycling of cancer cells exhibiting a stem cell-like phenotype, such as AH130 cells. This may impact the therapeutic use of MTX and of folates as supportive care.
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Affiliation(s)
- Maria Grazia Cipolleschi
- a Department of Experimental and Clinical Biomedical Sciences "Mario Serio ," Università degli Studi di Firenze , Florence , Italy
| | - Ilaria Marzi
- a Department of Experimental and Clinical Biomedical Sciences "Mario Serio ," Università degli Studi di Firenze , Florence , Italy
| | - Elisabetta Rovida
- a Department of Experimental and Clinical Biomedical Sciences "Mario Serio ," Università degli Studi di Firenze , Florence , Italy
| | - Massimo Olivotto
- a Department of Experimental and Clinical Biomedical Sciences "Mario Serio ," Università degli Studi di Firenze , Florence , Italy
| | - Persio Dello Sbarba
- a Department of Experimental and Clinical Biomedical Sciences "Mario Serio ," Università degli Studi di Firenze , Florence , Italy
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MTHFR c.677C>T Inhibits Cell Proliferation and Decreases Prostate Cancer Susceptibility in the Han Chinese Population in Shanghai. Sci Rep 2016; 6:36290. [PMID: 27819322 PMCID: PMC5098242 DOI: 10.1038/srep36290] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 10/13/2016] [Indexed: 12/15/2022] Open
Abstract
Methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C variants were known to be associated with prostate cancer (PCa) risk with conflicting results, because of MTHFR and nutrient status interaction in the prostate development. In this large-scale, hospital-based, case-control study of 1817 PCa cases and 2026 cancer-free controls, we aimed to clarify the association between these two MTHFR variants and PCa risk in Shanghai and to explore the underlying molecular mechanisms. We found that both the heterozygous CT (adjusted OR = 0.78, 95% CI: 0.67-0.92) and the homozygous TT genotypes (adjusted OR = 0.68, 95% CI: 0.55-0.83) of c.677C>T were associated with a significantly decreased risk of PCa compared with homozygous wild-type CC genotype, respectively, using multivariate logistic regression. Furthermore, we confirmed that MTHFR c.677T allele was related to an increased serum homocysteine level in the Han Chinese population in Shanghai. In the cultured PCa cell lines, we observed that MTHFR c.677T could elevate the cellular homocysteine level and cause DNA damage, thus increasing cell apoptosis and finally inhibiting cell proliferation. In conclusion, MTHFR c.677T was a protective factor of PCa risk in ethnic Han Chinese males by inducing DNA damage and cell apoptosis.
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Abstract
Food fortified with folic acid has been available for consumption in North America for over a decade. This strategy has led to an increase in folate levels in the general population and, more importantly, a significant decrease in the incidence of neural tube defects. However, this increase in folate intake has been associated with a greater risk of cancer disease. Many African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. A precedent for such a concern is the now compelling evidence showing that an increase in iron intake can lead to a higher malaria risk; as a result, mass administration of iron in malaria-endemic areas is not recommended. In this article, we review work on the effect of folate on malaria parasites. Although this topic has received little research attention, the available data suggest that the increase in folate concentration could be associated with an increase in malaria infection. Thus, the introduction of food fortification with folic acid in malaria-endemic areas should be attended by precautionary programs to monitor the risk of malaria.
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Affiliation(s)
- Alexis Nzila
- Department of Life Sciences, King Fahd University of Petroleum and Minerals, Dhahran, Saudi Arabia
| | - John Okombo
- University of Cape Town, Cape Town, South Africa
| | - John Hyde
- Manchester Institute of Biotechnology (MIB), Manchester, United Kingdom
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25
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Bayne CE, Jarrett TW. Cancer of the Prostate: Incidence in the USA. Prostate Cancer 2016. [DOI: 10.1016/b978-0-12-800077-9.00014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Labbé DP, Zadra G, Ebot EM, Mucci LA, Kantoff PW, Loda M, Brown M. Role of diet in prostate cancer: the epigenetic link. Oncogene 2015; 34:4683-91. [PMID: 25531313 PMCID: PMC4476943 DOI: 10.1038/onc.2014.422] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/28/2014] [Accepted: 11/03/2014] [Indexed: 12/12/2022]
Abstract
Diet is hypothesized to be a critical environmentally related risk factor for prostate cancer (PCa) development, and specific diets and dietary components can also affect PCa progression; however, the mechanisms underlying these associations remain elusive. As for a maturing organism, PCa's epigenome is plastic and evolves from the pre-neoplastic to the metastatic stage. In particular, epigenetic remodeling relies on substrates or cofactors obtained from the diet. Here we review the evidence that bridges dietary modulation to alterations in the prostate epigenome. We propose that such diet-related effects offer a mechanistic link between the impact of different diets and the course of PCa development and progression.
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Affiliation(s)
- D P Labbé
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - G Zadra
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - E M Ebot
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - L A Mucci
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
- Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - P W Kantoff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - M Loda
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - M Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
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Donnenfeld M, Deschasaux M, Latino-Martel P, Diallo A, Galan P, Hercberg S, Ezzedine K, Touvier M. Prospective association between dietary folate intake and skin cancer risk: results from the Supplémentation en Vitamines et Minéraux Antioxydants cohort. Am J Clin Nutr 2015; 102:471-8. [PMID: 26156743 DOI: 10.3945/ajcn.115.109041] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 05/27/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The role of folate in skin carcinogenesis is unclear, with experimental data suggesting potentially protective but also deleterious effects. OBJECTIVE Our main objective was to investigate the prospective association between dietary folate intake and risks of skin cancer (overall), nonmelanoma skin cancer (NMSC), and basal cell carcinoma (BCC). As an exploratory analysis, we also investigated the prospective association between erythrocyte folate concentration and skin cancer risk. DESIGN In this study, we included 5880 participants in the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort (follow-up: 1994-2007) who completed at least six 24-h dietary records during the first 2 y of the study. Associations between sex-specific tertiles of dietary and erythrocyte folate and skin cancer risk were assessed by using multivariate Cox proportional hazards models. RESULTS After a median follow-up of 12.6 y, 144 incident skin cancers were diagnosed. Dietary folate intake was associated with increased risk of overall skin cancer [HR for tertile 3 compared with tertile 1 (HR(T3vs.T1)): 1.79; 95% CI: 1.07, 2.99; P-trend = 0.03], NMSC (HR(T3vs.T1): 1.85; 95% CI: 1.06, 3.23; P-trend = 0.03), and BCC (HR(T3vs.T1): 1.78; 0.98, 3.24; P-trend = 0.05). This association was observed in women (corresponding P-trend = 0.007, 0.009, and 0.009, respectively) but not in men (P-trend = 0.8, 0.8, and 0.9, respectively). P-interaction values between tertiles of dietary folate intake and sex were 0.04, 0.02, and 0.02 for overall skin cancer, NMSC, and BCC, respectively. Erythrocyte folate concentration was directly associated with increased risk of overall skin cancer (HR(T3vs.T1): 2.54; 95% CI: 0.95, 6.81; P-trend = 0.03), NMSC (HR(T3vs.T1): 3.49; 95% CI: 1.11, 11.0; P-trend = 0.01), and BCC (HR(T3vs.T1): 7.44; 95% CI: 1.57, 35.3; P-trend = 0.004) (men and women combined). CONCLUSIONS This prospective study suggests an association between dietary folate intake and erythrocyte folate concentration and increased risk of overall skin cancer, NMSC, and BCC. Although several mechanistic hypotheses and 2 previous large prospective studies on BCC are in line with these results, epidemiologic literature is limited, and future research is needed to better elucidate the potential role of folate in the cause of skin cancers.
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Affiliation(s)
- Mathilde Donnenfeld
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France
| | - Mélanie Deschasaux
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France
| | - Paule Latino-Martel
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France
| | - Abou Diallo
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France
| | - Pilar Galan
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France
| | - Serge Hercberg
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France; Public Health Department, Avicenne Hospital, Bobigny, France; and
| | - Khaled Ezzedine
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France; Dermatology Department, Saint André Hospital, Bordeaux, France
| | - Mathilde Touvier
- Sorbonne Paris Cité Epidemiology and Biostatistics Research Center, French National Institute of Health and Medical Research U1153, French National Institute for Agricultural Research U1125, Cnam, Paris 13 University, Nutritional Epidemiology Research Team, Bobigny, France;
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Rycyna KJ, Bacich DJ, O'Keefe DS. Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States. Clin Nutr 2015. [PMID: 26205320 DOI: 10.1016/j.clnu.2015.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS As part of a broader study examining the relationship between serum folate concentrations and prostate cancer progression, we determined if there are age related changes in serum folate concentration compared to folate intake in the U.S. male population. METHODS Weighted data from the 2007-2008 and 2009-2010 NHANES databases was analyzed. A subpopulation of male participants was selected who were older than one year of age, had completed two days of dietary recall including supplement usage, and had fasted for at least 4 h prior to having their serum folate measured. Total dietary folate equivalent (DFE) intake (mcg) represented the combination of all natural food folate and folic acid from fortification and dietary supplements. Geometric means of serum folate (nM), red blood cell (RBC) folate (nM), and DFE intake were calculated for nine consecutive age groups, with each group generally representing a 10 year span. Analysis was then focused on males older than 20 years of age. RESULTS A total of 19,142 subjects were in the initial NHANES population, which represented over 294 million people within the United States. Applying our inclusion criteria created a final subpopulation size of 3775. Subsequent analysis of the age groups for all males older than 20 years found the following: The mean serum folate (nM) with 95% CI levels ranged from 28.2 (26.6, 29.9) to 55.1 (47.5, 63.9). RBC folate (nM) concentrations with 95% CI levels without any fasting exclusions ranged from 795.6 (741.5, 853.7) to 1038.4 (910.7, 1184.2). Serum and RBC folate concentrations were significantly higher with age across these age groups (p < 0.001). However, the mean total daily DFE intake did not significantly differ ranging from 640.4 (574.7, 713.7) to 720.2 (665, 780) mcg, (p = 0.373). Serum folate concentrations in men with total daily DFE intake of at least 1000 mcg increased more significantly with increasing age than serum folate concentrations in men with less than 400 mcg of total daily DFE intake (p < 0.001). There was a similar trend with the RBC folate concentrations (p = 0.054). CONCLUSIONS We observed higher serum and RBC folate concentrations and a divergence between dietary folate intake and these folate concentrations in older males. This phenomenon was evident at total DFE intakes that were significantly less than the 1000 mcg tolerable upper intake level currently recommended by the Institute of Medicine.
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Affiliation(s)
- Kevin J Rycyna
- Department of Urology, University of Pittsburgh Medical Center, United States
| | - Dean J Bacich
- Department of Urology, University of Texas Health Science Center at San Antonio, United States.
| | - Denise S O'Keefe
- Department of Urology, University of Texas Health Science Center at San Antonio, United States
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Lin PH, Aronson W, Freedland SJ. Nutrition, dietary interventions and prostate cancer: the latest evidence. BMC Med 2015; 13:3. [PMID: 25573005 PMCID: PMC4286914 DOI: 10.1186/s12916-014-0234-y] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 11/11/2014] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer (PCa) remains a leading cause of mortality in US men and the prevalence continues to rise world-wide especially in countries where men consume a 'Western-style' diet. Epidemiologic, preclinical and clinical studies suggest a potential role for dietary intake on the incidence and progression of PCa. 'This minireview provides an overview of recent published literature with regard to nutrients, dietary factors, dietary patterns and PCa incidence and progression. Low carbohydrates intake, soy protein, omega-3 (w-3) fat, green teas, tomatoes and tomato products and zyflamend showed promise in reducing PCa risk or progression. A higher saturated fat intake and a higher β-carotene status may increase risk. A 'U' shape relationship may exist between folate, vitamin C, vitamin D and calcium with PCa risk. Despite the inconsistent and inconclusive findings, the potential for a role of dietary intake for the prevention and treatment of PCa is promising. The combination of all the beneficial factors for PCa risk reduction in a healthy dietary pattern may be the best dietary advice. This pattern includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats, and reduced cooked meats. Further carefully designed prospective trials are warranted.
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Affiliation(s)
- Pao-Hwa Lin
- Department of Medicine, Division of Nephrology, Duke University Medical Center, Box 3487, Durham, NC 27710 USA
| | - William Aronson
- Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA USA
- Department of Urology, UCLA School of Medicine, Los Angeles, CA USA
| | - Stephen J Freedland
- Urology Section, Department of Surgery, Durham Veterans Affairs Medical Center, Division of Urology, Durham, NC USA
- Duke Prostate Center, Departments of Surgery and Pathology, Duke University Medical Center, Durham, NC USA
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Aragón F, Perdigón G, LeBlanc ADMD. Modification in the diet can induce beneficial effects against breast cancer. World J Clin Oncol 2014; 5:455-464. [PMID: 25114859 PMCID: PMC4127615 DOI: 10.5306/wjco.v5.i3.455] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The population tends to consume foods that in addition to their nutritional values can offer some benefits to their health. There are many epidemiological evidences and research studies in animal models suggesting that diet plays an important role in breast cancer prevention or progression. This review summarized some of the relevant researches about nutrition and cancer during the last years, especially in breast cancer. The analysis of probiotics and fermented products containing lactic acid bacteria in cancer prevention and/or treatment was especially discussed. It was observed that a balance of fatty acids similar to those of traditional Mediterranean diet, the consumption of fruits and vegetables, dietary fiber intake, vitamin supplementation are, along with the intake of probiotic products, the most extensively studied by the negative association to breast cancer risk. The consumption of probiotics and fermented products containing lactic acid bacteria was associated to reduce breast cancer risk in some epidemiological studies. The use of animal models showed the modulation of the host’s immune response as one of the important effects associated to the benefices observed with most probiotics. However; future assays in human are very important before the medical community can accept the addition of probiotic or fermented milks containing lactic acid bacteria as supplements for cancer patients.
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