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Xu N, Lin H, Ding X, Wang P, Lin JM. Isotope tracing-assisted chip-based solid-phase extraction mass spectrometry for monitoring metabolic changes and vitamin D3 regulation in cells. Talanta 2025; 288:127754. [PMID: 39970803 DOI: 10.1016/j.talanta.2025.127754] [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: 01/13/2025] [Revised: 02/11/2025] [Accepted: 02/15/2025] [Indexed: 02/21/2025]
Abstract
Cellular metabolism is a dynamic and essential process, with alterations in metabolic pathways serving as hallmark features of cancer. In this study, we developed a chip-based solid-phase extraction mass spectrometry (Chip-SPE-MS) platform for high-sensitivity, high-throughput analysis of cellular metabolites and real-time tracking of metabolic fluxes. The system achieved detection limits ranging from 0.10 to 9.43 μmol/mL for various amino acids and organic acids, with excellent linearity (r ≥ 0.992). By incorporating isotope tracing, the platform enabled derivatization-free, real-time monitoring of 13C-labeled metabolites, such as lactic acid. Our analysis revealed significant metabolic differences between normal (L02) and cancerous (HepG2, HCT116) cells, including enhanced glycolytic activity and elevated lactate production in cancer cells. Furthermore, treatment with 1,25-dihydroxyvitamin D3 was shown to suppress glucose uptake and modulate metabolic activity in HCT116 cells, highlighting the regulatory effects of vitamin D3 on cancer metabolism. This study not only provides novel insights into the metabolic reprogramming associated with cancer but also demonstrates the potential of the Chip-SPE-MS platform as a powerful tool for real-time monitoring of dynamic metabolic processes. The findings have broad implications for cancer therapy and the study of metabolic diseases.
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Affiliation(s)
- Ning Xu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Haifeng Lin
- Department of Bioengineering, Beijing Technology and Business University, Beijing, 100048, China
| | - Xiaodan Ding
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Peilong Wang
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
| | - Jin-Ming Lin
- Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.
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Du W, Xu C, Cheng Z, Sun Z, Guo S, Li Q, Song Y, Shen B, Bao Y, Wu J. Significance of TYMS Polymorphism rs3819102 as a Prognostic Marker for Nonsmoking Lung Cancer Patients of the Han Ethnicity in China. Oncology 2025:1-11. [PMID: 39879964 DOI: 10.1159/000542660] [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: 06/23/2024] [Accepted: 10/22/2024] [Indexed: 01/31/2025]
Abstract
INTRODUCTION With high incidence and mortality rates, lung cancer is now one of the most common cancers in the world. The 5-year survival rate of lung cancer patients is very low, and predicting the prognosis of lung cancer patients and using it to develop treatment strategies and interventions is important for prolonging the survival time of patients. Folate metabolism involves various aspects such as methylation of DNA, RNA, proteins, lipids, etc. Disorders of folate metabolism are closely related to cardiovascular diseases, immunodeficiencies, tumors, etc., and TYMS is a key enzyme in the folate metabolic pathway. We investigated and analyzed the relationship between single nucleotide polymorphism rs3819102 synergistic clinical features in the TYMS and prognosis in lung cancer. METHODS A total of 888 Han Chinese patients with primary lung cancer were recruited between January and November 2009 (10 months), including Changhai Hospital Affiliated to the Naval Military Medical university (Second Military Medical University) and Taizhou Institute of Health Sciences of Fudan University. Of these, 49 were excluded due to incomplete data collected for various reasons. The study was approved by the Ethics Committee of the School of Life Sciences, Fudan University, and written informed consent was obtained from all participating subjects. This study does not include minors. Genomic DNA was extracted from patient blood samples using the Qiagen Blood Kit (Qiagen, Chatsworth, California) and genotyped using SNPscan technology. The association between TYMS polymorphism rs3819102 and prognostic was analyzed by the Kaplan-Meier (KM) analysis, log-rank test, and Cox proportional-hazards model. RESULTS In the Han nationality nonsmoking patients in China, compared with AA + AG genotype, the GG genotype (GG vs. AA + AG: adjusted hazard ratio = 1.69, 95% confidence interval: 1.00-2.83, p = 0.048401) of rs3819102 conferred a worse prognosis. TYMS rs3819102 A > G mutation shortened lung cancer patients' survival and worse prognosis. CONCLUSION TYMS rs3819102 may be a prognostic factor for deterioration in lung cancer patients.
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Affiliation(s)
- Wei Du
- College of Basic Medicine, Naval Medical University, Shanghai, China
| | - Chang Xu
- Clinical College of Xiangnan University, Chenzhou, China
| | - Zhiyuan Cheng
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenyu Sun
- Department of Traditional Chinese Medicine, Naval Medical University, Shanghai, China
| | - Shicheng Guo
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Qiang Li
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bo Shen
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yang Bao
- Department of Thoracic Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Junjie Wu
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Geriatric Medical Center, Shanghai, China
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Pereira F, Fernández-Barral A, Larriba MJ, Barbáchano A, González-Sancho JM. From molecular basis to clinical insights: a challenging future for the vitamin D endocrine system in colorectal cancer. FEBS J 2024; 291:2485-2518. [PMID: 37699548 DOI: 10.1111/febs.16955] [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: 05/15/2023] [Revised: 08/03/2023] [Accepted: 09/11/2023] [Indexed: 09/14/2023]
Abstract
Colorectal cancer (CRC) is one of the most life-threatening neoplasias in terms of incidence and mortality worldwide. Vitamin D deficiency has been associated with an increased risk of CRC. 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active vitamin D metabolite, is a pleiotropic hormone that, through its binding to a transcription factor of the nuclear receptor superfamily, is a major regulator of the human genome. 1,25(OH)2D3 acts on colon carcinoma and stromal cells and displays tumor protective actions. Here, we review the variety of molecular mechanisms underlying the effects of 1,25(OH)2D3 in CRC, which affect multiple processes that are dysregulated during tumor initiation and progression. Additionally, we discuss the epidemiological data that associate vitamin D deficiency and CRC, and the most relevant randomized controlled trials of vitamin D3 supplementation conducted in both healthy individuals and CRC patients.
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Affiliation(s)
- Fábio Pereira
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Ourense, Spain
| | - Asunción Fernández-Barral
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - María Jesús Larriba
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - Antonio Barbáchano
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
| | - José Manuel González-Sancho
- Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz-IdiPAZ (Hospital Universitario La Paz-Universidad Autónoma de Madrid), Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Gelineau-van Waes J, van Waes MA, Hallgren J, Hulen J, Bredehoeft M, Ashley-Koch AE, Krupp D, Gregory SG, Stessman HA. Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir. Front Cell Dev Biol 2023; 11:1175917. [PMID: 37377737 PMCID: PMC10292217 DOI: 10.3389/fcell.2023.1175917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
In 2018, data from a surveillance study in Botswana evaluating adverse birth outcomes raised concerns that women on antiretroviral therapy (ART) containing dolutegravir (DTG) may be at increased risk for neural tube defects (NTDs). The mechanism of action for DTG involves chelation of Mg2+ ions in the active site of the viral integrase. Plasma Mg2+ homeostasis is maintained primarily through dietary intake and reabsorption in the kidneys. Inadequate dietary Mg2+ intake over several months results in slow depletion of plasma Mg2+ and chronic latent hypomagnesemia, a condition prevalent in women of reproductive age worldwide. Mg2+ is critical for normal embryonic development and neural tube closure. We hypothesized that DTG therapy might slowly deplete plasma Mg2+ and reduce the amount available to the embryo, and that mice with pre-existing hypomagnesemia due to genetic variation and/or dietary Mg2+ insufficiency at the time of conception and initiation of DTG treatment would be at increased risk for NTDs. We used two different approaches to test our hypothesis: 1) we selected mouse strains that had inherently different basal plasma Mg2+ levels and 2) placed mice on diets with different concentrations of Mg2+. Plasma and urine Mg2+ were determined prior to timed mating. Pregnant mice were treated daily with vehicle or DTG beginning on the day of conception and embryos examined for NTDs on gestational day 9.5. Plasma DTG was measured for pharmacokinetic analysis. Our results demonstrate that hypomagnesemia prior to conception, due to genetic variation and/or insufficient dietary Mg2+ intake, increases the risk for NTDs in mice exposed to DTG. We also analyzed whole-exome sequencing data from inbred mouse strains and identified 9 predicted deleterious missense variants in Fam111a that were unique to the LM/Bc strain. Human FAM111A variants are associated with hypomagnesemia and renal Mg2+ wasting. The LM/Bc strain exhibits this same phenotype and was the strain most susceptible to DTG-NTDs. Our results suggest that monitoring plasma Mg2+ levels in patients on ART regimens that include DTG, identifying other risk factors that impact Mg2+ homeostasis, and correcting deficiencies in this micronutrient might provide an effective strategy for mitigating NTD risk.
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Affiliation(s)
- J. Gelineau-van Waes
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | | | - J. Hallgren
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - J. Hulen
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - M. Bredehoeft
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - A. E. Ashley-Koch
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States
| | - D. Krupp
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - S. G. Gregory
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | - H. A. Stessman
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
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Ma SC, Zhang JQ, Yan TH, Miao MX, Cao YM, Cao YB, Zhang LC, Li L. Novel strategies to reverse chemoresistance in colorectal cancer. Cancer Med 2023. [PMID: 36645225 DOI: 10.1002/cam4.5594] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 12/02/2022] [Accepted: 12/21/2022] [Indexed: 01/17/2023] Open
Abstract
Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.
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Affiliation(s)
- Shu-Chang Ma
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Jia-Qi Zhang
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tian-Hua Yan
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Ming-Xing Miao
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Ye-Min Cao
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-Bing Cao
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li-Chao Zhang
- Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Ling Li
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kumar A, Singh AK, Singh H, Thareja S, Kumar P. Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:3. [PMID: 36308643 DOI: 10.1007/s12032-022-01864-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/29/2022] [Indexed: 01/17/2023]
Abstract
Thymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/β catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells.
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Affiliation(s)
- Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India.
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Aslam A, Ahmad J, Baghdadi MA, Idris S, Almaimani R, Alsaegh A, Alhadrami M, Refaat B. Chemopreventive effects of vitamin D 3 and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules. Biochim Biophys Acta Mol Basis Dis 2020; 1867:166040. [PMID: 33338596 DOI: 10.1016/j.bbadis.2020.166040] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/07/2020] [Accepted: 12/09/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca2+)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca2+-mediated apoptosis in vivo and in vitro. METHODS Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD3 (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD3, Pcal and/or 5-FU were applied in the HT29 colon cancer cells. RESULTS The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca2+ concentrations and Ca2+-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca2+ levels and Ca2+-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca2+-related molecules at the gene and protein levels in vivo and in vitro. CONCLUSIONS VD3 was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca2+-related molecules involved in tumour suppression.
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Affiliation(s)
- Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | | | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Riyad Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | - Aiman Alsaegh
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia
| | - Mai Alhadrami
- Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia.
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Story MJ. Zinc, ω-3 polyunsaturated fatty acids and vitamin D: An essential combination for prevention and treatment of cancers. Biochimie 2020; 181:100-122. [PMID: 33307154 DOI: 10.1016/j.biochi.2020.11.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 11/14/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
Zinc, ω-3 polyunsaturated fatty acids (PUFAs) and vitamin D are essential nutrients for health, maturation and general wellbeing. Extensive literature searches have revealed the widespread similarity in molecular biological properties of zinc, ω-3 PUFAs and vitamin D, and their similar anti-cancer properties, even though they have different modes of action. These three nutrients are separately essential for good health, especially in the aged. Zinc, ω-3 PUFAs and vitamin D are inexpensive and safe as they are fundamentally natural and have the properties of correcting and inhibiting undesirable actions without disturbing the normal functions of cells or their extracellular environment. This review of the anticancer properties of zinc, ω-3 PUFAs and vitamin D is made in the context of the hallmarks of cancer. The anticancer properties of zinc, ω-3 PUFAs and vitamin D can therefore be used beneficially through combined treatment or supplementation. It is proposed that sufficiency of zinc, ω-3 PUFAs and vitamin D is a necessary requirement during chemotherapy treatment and that clinical trials can have questionable integrity if this sufficiency is not checked and maintained during efficacy trials.
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Affiliation(s)
- Michael J Story
- Story Pharmaceutics Pty Ltd, PO Box 6086, Linden Park, South Australia, 5065, Australia.
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Songyang Y, Song T, Shi Z, Li W, Yang S, Li D. Effect of vitamin D on malignant behavior of non-small cell lung cancer cells. Gene 2020; 768:145309. [PMID: 33197518 DOI: 10.1016/j.gene.2020.145309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 10/26/2020] [Accepted: 11/10/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To investigate the effects of vitamin D on the malignant behavior of A549 and NCI-H1975 tumor cells (proliferation, apoptosis, invasion, metastasis and drug resistance-related proteins) and the activation of the PI3K/AKT/mTOR signaling pathway, in order to evaluate the effect of vitamin D on the therapeutic action of cisplatin. METHOD In vitro cell experiments, CCK-8, flow cytometry, transwell, scratches, MTT and Western blot were used to reveal the effect of vitamin D on non-small cell lung cancer (NSCLC), and the expression of PI3K/AKT/mTOR signaling pathway was also detected. In vivo animal experiments, the nude mice were divided into four groups: control group, vitamin D treatment group, cisplatin treatment group and vitamin D + cisplatin combined treatment group. After tumor formation in vitro, tumor volume changes were calculated and tumor growth curves were drawn, collected tumor tissues for pathological sections. Western blot was used to detect the expression changes of drug-resistance related proteins in tumor tissues. Meanwhile, protein expression changes of PI3K/AKT/mTOR signaling pathway in tumor tissues were detected. RESULT In vitro experiments confirm Vitamin D can inhibit the proliferation, invasion and metastasis of non-small cell lung cancer cells A549 and NCI-H1975, promoting cell apoptosis, up-regulate the sensitivity of chemotherapy drugs. These effects of vitamin D may be correlated with the PI3K/AKT/mTOR signaling pathway. In vivo animal experiments, the changes in tumor volume, tumor inflammatory infiltration range, expression of drug-resistant related proteins and signaling pathway related proteins in mice were as follows: The vitamin D and cisplatin combined treatment group was significantly smaller than the control group. CONCLUSION Vitamin D can inhibit the proliferation, invasion and metastasis of non-small cell lung cancer (NSCLC) cells A549 and NCI-H1975 and promote apoptosis, up-regulate the sensitivity of chemotherapy drugs. The effect of vitamin D on NSCLC cells A549 and NCI-H1975 was correlated with the PI3K/AKT/mTOR signaling pathway. Vitamin D also promotes the therapeutic effect of CDDP.
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Affiliation(s)
- Yiyan Songyang
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, China
| | - Tianbao Song
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuhan, China
| | - Zhan Shi
- Human Biology Program, University of Toronto, ON M5S 3J6, Canada
| | - Wen Li
- Renmin Hospital of Wuhan University, Department of Emergency, Wuhan, China
| | - Songyisha Yang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Dejia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, China.
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Xie P, Mo JL, Liu JH, Li X, Tan LM, Zhang W, Zhou HH, Liu ZQ. Pharmacogenomics of 5-fluorouracil in colorectal cancer: review and update. Cell Oncol (Dordr) 2020; 43:989-1001. [PMID: 32474853 DOI: 10.1007/s13402-020-00529-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/20/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a disease with high morbidity and mortality rates. 5-fluorouracil (5-FU) is the first-line recommended drug for chemotherapy in patients with CRC, and it has a good effect on a variety of other solid tumors as well. Unfortunately, however, due to the emergence of drug resistance the effectiveness of treatment may be greatly reduced. In the past decade, major progress has been made in the field of 5-FU drug resistance in terms of molecular mechanisms, pre-clinical (animal) models and clinical trials. CONCLUSIONS In this article we systematically review and update current knowledge on 5-FU pharmacogenomics related to drug uptake and activation, the expression and activity of target enzymes (DPD, TS and MTHFR) and key signaling pathways in CRC. Furthermore, a summary of drug combination strategies aimed at targeting specific genes and/or pathways to reverse 5-FU resistance is provided. Based on this, we suggest that causal relationships between genes, pathways and drug sensitivity should be systematically considered from a multidimensional perspective. In the design of research methods, emerging technologies such as CRISPR-Cas, TALENS and patient-derived xenograft models should be applied as far as possible to improve the accuracy of clinically relevant results.
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Affiliation(s)
- Pan Xie
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Jun-Luan Mo
- Shenzhen Center for Chronic Disease Control, 518020, Shenzhen, People's Republic of China
| | - Jin-Hong Liu
- Shenzhen Center for Chronic Disease Control, 518020, Shenzhen, People's Republic of China
| | - Xi Li
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Li-Ming Tan
- Department of Pharmacy, The Second People's Hospital of Huaihua City, 418000, Huaihua, People's Republic of China
| | - Wei Zhang
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China. .,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China.
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12
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Vitamin D Levels in Patients with Colorectal Cancer Before and After Treatment Initiation. J Gastrointest Cancer 2020; 50:769-779. [PMID: 30058032 DOI: 10.1007/s12029-018-0147-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE We aimed to described 25-hydroxyvitamin D [25(OH)D] levels in newly diagnosed colorectal cancer (CRC) patients and to re-evaluate levels after chemotherapy. METHODS Permanent residents of the San Francisco Bay Area with a new CRC diagnosis of any stage were recruited prior to any non-surgical therapy. Serum 25(OH)D levels were measured at time of diagnosis and 6-month follow-up. Supplement use was not restricted. The primary endpoint was the frequency of vitamin D deficiency in patients with newly diagnosed CRC of all stages. The Kruskal-Wallis and Spearman correlation tests were used to evaluate associations of patient characteristics with 25(OH)D levels. RESULTS Median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2, 59.0); 65% of patients had insufficient levels (25(OH)D < 30 ng/mL) (n = 94). Race, disease stage, multivitamin use, vitamin D supplementation, and county of residence were associated with baseline 25(OH)D levels (P < 0.05). The median change in 25(OH)D from baseline to 6 months was - 0.7 ng/mL [- 19.4, 51.7] for patients treated with chemotherapy (n = 58) and 1.6 ng/mL [- 6.4, 33.2] for patients who did not receive chemotherapy (n = 19) (P = 0.26). For patients who received vitamin D supplementation during chemotherapy, the median 25(OH)D change was 8.3 ng/mL [- 7.6, 51.7] versus - 1.6 [- 19.4, 24.3] for chemotherapy patients who did not take vitamin D supplements (P = 0.02). CONCLUSION Among patients with a new diagnosis of CRC, most patients were found to have 25(OH)D levels consistent with either deficiency or insufficiency. In the subset of patients who received chemotherapy and took a vitamin D supplement, serum 25(OH)D levels increased, suggesting that vitamin D repletion is a feasible intervention during chemotherapy.
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13
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Haidari F, Abiri B, Iravani M, Razavi SM, Sarbakhsh P, Ahmadi-Angali K, Vafa M. Effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory biomarkers, tumor marker CEA, and nutritional status in patients with colorectal cancer: a study protocol for a double blind randomized controlled trial. Trials 2019; 20:682. [PMID: 31815661 PMCID: PMC6900845 DOI: 10.1186/s13063-019-3719-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 09/13/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Much evidence is available demonstrating that both vitamin D and omega-3 fatty acids block the development and progression of colonic carcinogenesis. The results of animal studies have shown that the consumption of omega-3 fatty acids can decrease inflammatory biomarkers, enhance the efficacy of chemotherapy, and decrease the side effects of chemotherapy or cancer. Also, observational studies propose that higher levels of 25(OH)D are related to improved survival of colorectal cancer patients. This study will aim to evaluate the effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory biomarkers, tumor marker CEA, and nutritional status in colorectal cancer patients. METHODS/DESIGN We will carry out an 8-week double-blind randomized, placebo-controlled clinical trial to evaluate the effects of vitamin D and omega-3 fatty acids co-supplementation on inflammatory biomarkers, tumor marker CEA, and nutritional status in patients with stage ӀӀ or ӀӀӀ colorectal cancer undergoing chemotherapy. DISCUSSION Because of the important effects of vitamin D and omega-3 fatty acids on molecular pathways involved in cancer development and progression, it seems that both vitamin D and omega-3 fatty acids may provide a new adjuvant therapy by decreasing inflammatory biomarkers and resistance to cancer treatment in patients with colorectal cancer. TRIAL REGISTRATION Iranian Registry of Clinical Trials IRCT20180306038979N1. Registered on 16 March 2018.
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Affiliation(s)
- Fatemeh Haidari
- Department of Nutrition, Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Behnaz Abiri
- Department of Nutrition, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masood Iravani
- Department of Oncology and Hematology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed-Mohsen Razavi
- Department of Oncology and Hematology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Parvin Sarbakhsh
- Department of Statistics and Epidemiology, School of Public Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kambiz Ahmadi-Angali
- Faculty of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammadreza Vafa
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran. .,Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran.
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14
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Milczarek M, Rossowska J, Klopotowska D, Stachowicz M, Kutner A, Wietrzyk J. Tacalcitol increases the sensitivity of colorectal cancer cells to 5-fluorouracil by downregulating the thymidylate synthase. J Steroid Biochem Mol Biol 2019; 190:139-151. [PMID: 30923017 DOI: 10.1016/j.jsbmb.2019.03.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 03/20/2019] [Accepted: 03/23/2019] [Indexed: 12/18/2022]
Abstract
5-Fluorouracil (5-FU) is an anticancer drug that is most frequently used to treat colorectal cancer (CRC) patients, but unfortunately it shows limited efficacy. We recently demonstrated that vitamin D analogs (VDAs), particularly tacalcitol (coded as PRI-2191), potentiate its anticancer activity in an in vivo mouse and human CRC model. The purpose of this study was to explain the mechanism underlying the enhancement of 5-FU efficacy by PRI-2191 towards human HT-29 CRC cells. We showed that PRI-2191 induces the CDKN1A (gene encoding p21Waf1/Cip1) expression directly through vitamin D receptor (VDR) in a p53-independent manner and thus decreases the thymidylate synthase expression both at the mRNA and protein level. It is the main mechanism by which PRI-2191 improves the anticancer efficacy of 5-FU towards HT-29 cells. Additionally, we indicated that the VDR also participates in 5-FU mechanism of action. 5-FU significantly increased TYMS (gene encoding thymidylate synthase (TS)) and BIRC5 (gene encoding survivin) level in HT-29 cells with silenced VDR. Furthermore, PRI-2191 induced E-cadherin and ZO-1 expression and thus reduced the level of BIRC5 in HT-29 cells. The induction of E-cadherin expression may also contribute to the reduction of c-Myc level and consequently the downregulation of TS. Our results also indicate that calcium-sensing receptor (CaSR) plays a role in the activity of PRI-2191 but has no influence on the 5-FU mechanism of action. In conclusion, we suggest that both VDR and CaSR might be useful as molecular markers for predicting treatment outcomes and identifying the CRC patient subgroups who might benefit from 5-FU-based chemotherapy combined with vitamin D analog.
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Affiliation(s)
- Magdalena Milczarek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland.
| | - Joanna Rossowska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Dagmara Klopotowska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Martyna Stachowicz
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Andrzej Kutner
- Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, 1 Banacha, 02-097, Warsaw, Poland
| | - Joanna Wietrzyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
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15
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Ng K, Nimeiri HS, McCleary NJ, Abrams TA, Yurgelun MB, Cleary JM, Rubinson DA, Schrag D, Miksad R, Bullock AJ, Allen J, Zuckerman D, Chan E, Chan JA, Wolpin BM, Constantine M, Weckstein DJ, Faggen MA, Thomas CA, Kournioti C, Yuan C, Ganser C, Wilkinson B, Mackintosh C, Zheng H, Hollis BW, Meyerhardt JA, Fuchs CS. Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA 2019; 321:1370-1379. [PMID: 30964527 PMCID: PMC6459117 DOI: 10.1001/jama.2019.2402] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
IMPORTANCE In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). OBJECTIVE To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). INTERVENTIONS mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. RESULTS Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). CONCLUSIONS AND RELEVANCE Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01516216.
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Affiliation(s)
- Kimmie Ng
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Halla S. Nimeiri
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois
| | | | | | | | | | | | | | - Rebecca Miksad
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | | | - Dan Zuckerman
- St Luke’s Mountain States Tumor Institute, Boise, Idaho
| | - Emily Chan
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | | | | | | | | | | | - Chen Yuan
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | | | | | - Hui Zheng
- Massachusetts General Hospital, Boston
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16
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Tang Q, Hu Z, Jin H, Zheng G, Yu X, Wu G, Liu H, Zhu Z, Xu H, Zhang C, Shen L. Microporous polysaccharide multilayer coated BCP composite scaffolds with immobilised calcitriol promote osteoporotic bone regeneration both in vitro and in vivo. Theranostics 2019; 9:1125-1143. [PMID: 30867820 PMCID: PMC6401415 DOI: 10.7150/thno.29566] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 01/14/2019] [Indexed: 12/16/2022] Open
Abstract
Incorporating a biomimetic coating and integrating osteoinductive biomolecules into basic bone substitutes are two common strategies to improve osteogenic capabilities in bone tissue engineering. Currently, the underlying mechanism of osteoporosis (OP)-related deficiency of osteogenesis remains unclear, and few treatments target at OP-related bone regeneration. Herein, we describe a self-assembling polyelectrolyte multilayered (PEM) film coating with local immobilisation of calcitriol (Cal) in biphasic calcium phosphate (BCP) scaffolds to promote osteoporotic bone regeneration by targeting the calcium sensing receptor (CaSR). Methods: The ovariectomy-induced functional changes in bone marrow mesenchymal stem cells (BMSCs), protective effects of Cal, and the potential mechanism were all verified. A PEM film composed of hyaluronic acid (HA) and chitosan (Chi) was prepared through layer-by-layer self-assembly. The morphology, growth behaviour, and drug retention capability of the composite scaffolds were characterised, and their biocompatibility and therapeutic efficacy for bone regeneration were systematically explored in vitro and in vivo.Results: The osteogenic differentiation, adhesion, and proliferation abilities of ovariectomised rat BMSCs (OVX-rBMSCs) decreased, in accordance with the deficiency of CaSR. Cal effectively activated osteogenesis in these OVX-rBMSCs by binding specifically to the active pocket of the CaSR structure, while the biomimetic PEM coating augmented OVX-rBMSCs proliferation and adhesion due to its porous surface structure. The PEM-coated scaffolds showed advantages in Cal loading and retention, especially at lower drug concentrations. HA/Chi PEM synergised with Cal to improve the proliferation, adhesion, and osteogenesis of OVX-rBMSCs and promote bone regeneration and BCP degradation in the critical-size calvarial bone defect model of OVX rats. Conclusion: A composite scaffold based on BCP, created by simply combining a biomimetic PEM coating and Cal immobilisation, could be clinically useful and has marked advantages as a targeted, off-the-shelf, cell-free treatment option for osteoporotic bone regeneration.
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Affiliation(s)
- Qian Tang
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- Department of Orthopaedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Zhichao Hu
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - Haiming Jin
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - Gang Zheng
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - XingFang Yu
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - Gang Wu
- Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), Vrije University Amsterdam and University of Amsterdam, Amsterdam, Nord-Holland, the Netherlands
| | - Haixiao Liu
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - Zhenzhong Zhu
- Department of Orthopaedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Huazi Xu
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
| | - Changqing Zhang
- Department of Orthopaedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Liyan Shen
- Key Laboratory of Orthopaedics of Zhejiang Province, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
- The second School of Medicine, Wenzhou Medical University, 109, Xueyuanxi road, 325027 Wenzhou, China
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Álvarez-Sala A, Ávila-Gálvez MÁ, Cilla A, Barberá R, Garcia-Llatas G, Espín JC, González-Sarrías A. Physiological concentrations of phytosterols enhance the apoptotic effects of 5-fluorouracil in colon cancer cells. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Hu N, Zhang H. CYP24A1 depletion facilitates the antitumor effect of vitamin D3 on thyroid cancer cells. Exp Ther Med 2018; 16:2821-2830. [PMID: 30233662 PMCID: PMC6143870 DOI: 10.3892/etm.2018.6536] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 03/14/2018] [Indexed: 02/06/2023] Open
Abstract
It has been demonstrated that 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1) is a key enzyme that neutralizes vitamin D activity, which may have an anti-tumor effect. Therefore, the aim of the current study was to explore the effect of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25-D3) on thyroid cancer cells following the downregulation of CYP24A1. A Cell Counting Kit-8 assay identified that CYP24A1 knockdown enhanced the anti-proliferative effects of 1,25-D3 on thyroid cancer cells. Furthermore, the results of the scratch wound and Transwell assays indicated that CYP24A1 knockdown enhanced the inhibitory effect of 1,25-D3 on cell migration. The results from reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that treatment with 1,25-D3 and CYP24A1 knockdown synergistically enhanced the expression of the epithelial-related gene E-cadherin and decreased the expression of the mesenchymal-related genes N-cadherin and vimentin. Following CYP24A1 knockdown and treatment with 1,25-D3, the expression of matrix metalloproteinase 2 and metalloproteinase inhibitor 1 were significantly decreased and increased, respectively, compared with the group that underwent treatment with 25-D3 alone. Furthermore, protein kinase B (Akt) and β-catenin activity was significantly decreased by this synergetic effect compared with the group that underwent treatment with 1,25-D3 alone. The results of the current study suggest that CYP24A1 knockdown contributes to the anti-tumor effect of 1,25-D3 and that this effect may be due to deactivation of the Akt and β-catenin signaling pathways. Therefore, CYP24A1 knockdown and 1,25-D3 treatment may be used synergistically as a novel therapeutic strategy to treat patients with thyroid cancer.
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Affiliation(s)
- Ning Hu
- The Second Sector of Department of Thyroid Breast Surgery, Southern Branch of Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
| | - Hao Zhang
- The First Sector of Department of Thyroid Breast Surgery, Northern Branch of Jingmen No. 1 People's Hospital, Jingmen, Hubei 448000, P.R. China
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19
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Barbáchano A, Larriba MJ, Ferrer-Mayorga G, González-Sancho JM, Muñoz A. Vitamin D and Colon Cancer. VITAMIN D 2018:837-862. [DOI: 10.1016/b978-0-12-809963-6.00099-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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The role of vitamin D in hepatic metastases from colorectal cancer. Clin Transl Oncol 2017; 20:259-273. [PMID: 28801869 DOI: 10.1007/s12094-017-1735-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 07/30/2017] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) represents a significant health burden worldwide, comprising approximately 10% of annual cancer cases globally. Hepatic metastases are the most common site of CRC metastasis, and are the leading cause of death in CRC patients. There is strong epidemiologic evidence for an inverse association between vitamin D status and risk of CRC; however, the role of vitamin D in the natural history of liver metastases has not yet been investigated. Several researchers have proposed hallmarks of metastases; crucially, metastases can be blocked by interrupting just one rate-limiting step. Vitamin D status has been implicated in each proposed hallmark of metastasis. The aim of this review is to examine the potential role for vitamin D in reducing the development of hepatic metastases from CRC and outline the candidate mechanisms by which vitamin D may mediate these effects. The results of ongoing randomised intervention trials are eagerly awaited to determine whether addressing vitamin D insufficiency in CRC patients could reduce the occurrence of liver metastases, and the consequent morbidity and mortality.
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21
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Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci 2017; 1376:29-52. [PMID: 27649525 DOI: 10.1111/nyas.13219] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 07/26/2016] [Accepted: 08/03/2016] [Indexed: 12/16/2022]
Abstract
The vitamin D receptor (VDR) is found in nearly all, if not all, cells in the body. The enzyme that produces the active metabolite of vitamin D and ligand for VDR, namely CYP27B1, likewise is widely expressed in many cells of the body. These observations indicate that the role of vitamin D is not limited to regulation of bone and mineral homeostasis, as important as that is. Rather, the study of its extraskeletal actions has become the major driving force behind the significant increase in research articles on vitamin D published over the past several decades. A great deal of information has accumulated from cell culture studies, in vivo animal studies, and clinical association studies that confirms that extraskeletal effects of vitamin D are truly widespread and substantial. However, randomized, placebo-controlled clinical trials, when done, have by and large not produced the benefits anticipated by the in vitro cell culture and in vivo animal studies. In this review, I will examine the role of vitamin D signaling in a number of extraskeletal tissues and assess the success of translating these findings into treatments of human diseases affecting those extracellular tissues.
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Affiliation(s)
- Daniel D Bikle
- Departments of Medicine and Dermatology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California.
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22
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Abstract
In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.
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Vitamin D and Physical Activity in Patients With Colorectal Cancer: Epidemiological Evidence and Therapeutic Implications. Cancer J 2017; 22:223-31. [PMID: 27341603 DOI: 10.1097/ppo.0000000000000197] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the United States. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients who received a diagnosis of localized disease ultimately have a recurrence and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as 2 potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the antineoplastic effects of vitamin D and PA, and a wealth of epidemiological evidence indicates that 25(OH)D (the main circulating form of vitamin D) and PA levels are inversely associated with CRC risk. Recent efforts have now focused on the role of vitamin D and PA as adjunct treatments after a CRC diagnosis. Observational studies evaluating prediagnosis and postdiagnosis circulating 25(OH)D levels among patients with CRC of all stages have found that subjects with levels in the highest quantiles have improved overall and CRC-specific survival compared with those with levels in the lowest quantiles. Similarly, prospective studies of PA have found that higher levels of postdiagnosis PA are associated with lower overall and CRC-specific mortality in patients with nonmetastatic CRC. Meta-analyses of the observational studies of 25(OH)D and postdiagnosis PA have confirmed significant protective associations against overall and CRC-specific mortality, as well as significant dose-response relationships. No randomized controlled trial of vitamin D or PA using survival outcomes as endpoints has been completed to date. Two randomized, placebo-controlled trials of vitamin D in patients with metastatic CRC assessing patient survival as an endpoint are underway: the first is a phase II trial comparing high-dose vitamin D3 (8000 IU/d for 2 weeks followed by 4000 IU/d) versus standard dose (400 IU/d), and the second is a phase I-II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80 to 100 ng/mL versus 2000 IU/d. For PA, the ongoing phase III CHALLENGE (Colon Health and Life-Long Exercise Change) study is the first randomized controlled trial using survival as an endpoint among patients with stage II-III colon cancer. The results of these trials will pave the way to more conclusive phase III trials that will provide more definitive answers about the role of these interventions in the treatment of CRC. Lastly, the advent of genomic technologies will allow identifying molecular signatures in CRC associated with improved response to vitamin D and PA and will usher in a precision medicine approach to these therapies.
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Aggarwal A, Kállay E. Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer. Front Physiol 2016; 7:451. [PMID: 27803671 PMCID: PMC5067519 DOI: 10.3389/fphys.2016.00451] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 09/21/2016] [Indexed: 12/25/2022] Open
Abstract
There is epidemiological evidence for the cancer preventive effect of dietary calcium (Ca2+) and vitamin D. This effect is strongest in colorectal cancer (CRC). The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D3), bound to its receptor, the vitamin D receptor (VDR) regulates the expression of hundreds of different genes in a cell- and tissue-specific manner. While Ca2+ acts through multiple mechanisms and pathways, some of its effects are mediated by the calcium-sensing receptor (CaSR). The joint action of Ca2+ and 1,25D3 is due to the fact that both regulate some of the main processes involved in the development of various cancers, such as proliferation, differentiation, apoptosis, migration, and inflammation. Moreover, 1,25D3, bound to VDR can induce translation of the CaSR, while the amount and activity of the CaSR affects 1,25D3 signaling. However, the complexity of the cross-talk between the CaSR and the vitamin D system goes beyond regulating similar pathways and affecting each other's expression. Our aim was to review some of the mechanisms that drive the cross-talk between the vitamin D system and the CaSR with a special focus on the interaction in CRC cells. We evaluated the molecular evidence that supports the epidemiological observation that both vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR.
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Affiliation(s)
- Abhishek Aggarwal
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of ViennaVienna, Austria; Department of Pediatrics/Endocrinology, School of Medicine, Stanford UniversityStanford, CA, USA
| | - Enikö Kállay
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna Vienna, Austria
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25
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Bikle DD, Jiang Y, Nguyen T, Oda Y, Tu CL. Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. Front Physiol 2016; 7:296. [PMID: 27462278 PMCID: PMC4940389 DOI: 10.3389/fphys.2016.00296] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/27/2016] [Indexed: 12/13/2022] Open
Abstract
1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis (epidVdr−∕− and epidCasr−∕−). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β–catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr−∕− mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the epidVdr−∕− or epidCasr−∕−. But in mice with epidermal specific deletion of both Vdr and Casr (epidVdr−∕−/epidCasr−∕− [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β–catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.
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Affiliation(s)
- Daniel D Bikle
- Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA
| | - Yan Jiang
- Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA
| | - Thai Nguyen
- Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA
| | - Yuko Oda
- Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA
| | - Chia-Ling Tu
- Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA
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Jeong S, Kim JH, Kim MG, Han N, Kim IW, Kim T, Oh JM. Genetic polymorphisms of CASR and cancer risk: evidence from meta-analysis and HuGE review. Onco Targets Ther 2016; 9:655-69. [PMID: 26929638 PMCID: PMC4755434 DOI: 10.2147/ott.s97602] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background CASR gene appears to be involved in cancer biology and physiology. However, a number of studies investigating CASR polymorphisms and cancer risks have presented inconclusive results. Thus, a systematic review and a meta-analysis of the effect of CASR polymorphisms on several cancer risks were performed to suggest a statistical evidence for the association of CASR polymorphisms with cancer risks. Methods MEDLINE, EMBASE, Web of Science, Scopus, and the HuGE databases were searched. Nineteen articles of case–control and cohort studies were included for the final analysis. Results The colorectal cancer risk was reduced in proximal (odds ratio [OR] =0.679, P=0.001) and distal (OR =0.753, P=0.026) colon sites with GG genotype of CASR rs1042636 and increased in distal colon site (OR =1.418, P=0.039) with GG genotype of rs1801726 by additive genetic model. The rs17251221 demonstrated noticeable associations that carrying a homozygote variant increases breast and prostate cancer risk considerably. Conclusion The significant association of CASR polymorphisms with several cancer risks was observed in this review. In particular, the act of CASR polymorphisms as a tumor suppressor or an oncogene differs by cancer site and can be the research target for tumorigenesis.
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Affiliation(s)
- Sohyun Jeong
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Jae Hyun Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Myeong Gyu Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Nayoung Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Therasa Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Jung Mi Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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27
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Ma Y, Johnson CS, Trump DL. Mechanistic Insights of Vitamin D Anticancer Effects. VITAMIN D HORMONE 2016; 100:395-431. [DOI: 10.1016/bs.vh.2015.11.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Aggarwal A, Höbaus J, Tennakoon S, Prinz-Wohlgenannt M, Graça J, Price SA, Heffeter P, Berger W, Baumgartner-Parzer S, Kállay E. Active vitamin D potentiates the anti-neoplastic effects of calcium in the colon: A cross talk through the calcium-sensing receptor. J Steroid Biochem Mol Biol 2016; 155:231-8. [PMID: 25758239 DOI: 10.1016/j.jsbmb.2015.02.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 02/09/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023]
Abstract
Epidemiological studies suggest an inverse correlation between dietary calcium (Ca(2+)) and vitamin D intake and the risk of colorectal cancer (CRC). It has been shown in vitro that the active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-D3) can upregulate expression of the calcium-sensing receptor (CaSR). In the colon, CaSR has been suggested to regulate proliferation of colonocytes. However, during tumorigenesis colonic CaSR expression is downregulated and we hypothesized that the loss of CaSR could influence the anti-tumorigenic effects of Ca(2+) and vitamin D. Our aim was to assess the impact of CaSR expression and function on the anti-neoplastic effects of 1,25-D3 in colon cancer cell lines. We demonstrated that in the healthy colon of mice, high vitamin D diet (2500 IU/kg diet) increased expression of differentiation and apoptosis markers, decreased expression of proliferation markers and significantly upregulated CaSR mRNA expression, compared with low vitamin D diet (100 IU/kg diet). To determine the role of CaSR in this process, we transfected Caco2-15 and HT29 CRC cells with wild type CaSR (CaSR-WT) or a dominant negative CaSR mutant (CaSR-DN) and treated them with 1,25-D3 alone, or in combination with CaSR activators (Ca(2+) and NPS R-568). 1,25-D3 enhanced the anti-proliferative effects of Ca(2+) and induced differentiation and apoptosis only in cells with a functional CaSR, which were further enhanced in the presence of NPS R-568, a positive allosteric modulator of CaSR. The mutant CaSR inhibited the anti-tumorigenic effects of 1,25-D3 suggesting that the anti-neoplastic effects of 1,25-D3 are, at least in part, mediated by the CaSR. Taken together, our data provides molecular evidence to support the epidemiological observation that both, vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Adenocarcinoma/prevention & control
- Aniline Compounds/pharmacology
- Animals
- Caco-2 Cells
- Calcium/metabolism
- Calcium/pharmacology
- Cell Differentiation/drug effects
- Cell Proliferation/drug effects
- Cell Transformation, Neoplastic/drug effects
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colon/drug effects
- Colon/metabolism
- Colon/pathology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- Colonic Neoplasms/prevention & control
- Dietary Supplements
- Gene Expression Regulation, Neoplastic
- HT29 Cells
- Humans
- Male
- Mice
- Mice, Transgenic
- Mutation
- Phenethylamines
- Propylamines
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Calcium-Sensing
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction
- Transfection
- Vitamin D/analogs & derivatives
- Vitamin D/pharmacology
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Affiliation(s)
- Abhishek Aggarwal
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Julia Höbaus
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Samawansha Tennakoon
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | | | - João Graça
- Safety Assessment, AstraZeneca, Macclesfield, UK
| | | | - Petra Heffeter
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Platform 'Translational Cancer Therapy Research', Vienna, Austria
| | - Walter Berger
- Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Platform 'Translational Cancer Therapy Research', Vienna, Austria
| | | | - Enikö Kállay
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
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Aggarwal A, Prinz-Wohlgenannt M, Tennakoon S, Höbaus J, Boudot C, Mentaverri R, Brown EM, Baumgartner-Parzer S, Kállay E. The calcium-sensing receptor: A promising target for prevention of colorectal cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1853:2158-67. [PMID: 25701758 PMCID: PMC4549785 DOI: 10.1016/j.bbamcr.2015.02.011] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 02/07/2015] [Accepted: 02/09/2015] [Indexed: 02/07/2023]
Abstract
The inverse correlation between dietary calcium intake and the risk of colorectal cancer (CRC) is well known, but poorly understood. Expression of the calcium-sensing receptor (CaSR), a calcium-binding G protein-coupled receptor is downregulated in CRC leading us to hypothesize that the CaSR has tumor suppressive roles in the colon. The aim of this study was to understand whether restoration of CaSR expression could reduce the malignant phenotype in CRC. In human colorectal tumors, expression of the CaSR negatively correlated with proliferation markers whereas loss of CaSR correlated with poor tumor differentiation and reduced apoptotic potential. In vivo, dearth of CaSR significantly increased expression of proliferation markers and decreased levels of differentiation and apoptotic markers in the colons of CaSR/PTH double knock-out mice confirming the tumor suppressive functions of CaSR. In vitro CRC cells stably overexpressing wild-type CaSR showed significant reduction in proliferation, as well as increased differentiation and apoptotic potential. The positive allosteric modulator of CaSR, NPS R-568 further enhanced these effects, whereas treatment with the negative allosteric modulator, NPS 2143 inhibited these functions. Interestingly, the dominant-negative mutant (R185Q) was able to abrogate these effects. Our results demonstrate a critical tumor suppressive role of CaSR in the colon. Restoration of CaSR expression and function is linked to regulation of the balance between proliferation, differentiation, and apoptosis and provides a rationale for novel strategies in CRC therapy.
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MESH Headings
- Amino Acid Substitution
- Aniline Compounds/pharmacology
- Animals
- Apoptosis/drug effects
- Apoptosis/genetics
- Caco-2 Cells
- Cell Differentiation/drug effects
- Cell Differentiation/genetics
- Cell Proliferation/drug effects
- Cell Proliferation/genetics
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Colorectal Neoplasms/prevention & control
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Male
- Mice
- Mice, Knockout
- Mutation, Missense
- Naphthalenes/pharmacology
- Phenethylamines
- Propylamines
- Receptors, Calcium-Sensing/antagonists & inhibitors
- Receptors, Calcium-Sensing/genetics
- Receptors, Calcium-Sensing/metabolism
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Tumor Suppressor Proteins/antagonists & inhibitors
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
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Affiliation(s)
- Abhishek Aggarwal
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | | | - Samawansha Tennakoon
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Julia Höbaus
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Cedric Boudot
- INSERM U1088, University of Picardie Jules Verne, Amiens, France
| | | | - Edward M Brown
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, USA
| | | | - Enikö Kállay
- Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.
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Berridge MJ. Vitamin D cell signalling in health and disease. Biochem Biophys Res Commun 2015; 460:53-71. [PMID: 25998734 DOI: 10.1016/j.bbrc.2015.01.008] [Citation(s) in RCA: 142] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/05/2015] [Indexed: 12/13/2022]
Abstract
Vitamin D deficiency has been linked to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. A Vitamin D phenotypic stability hypothesis, which is developed in this review, attempts to describe how this vital hormone acts to maintain healthy cellular functions. This role of Vitamin D as a guardian of phenotypic stability seems to depend on its ability to maintain the redox and Ca(2+) signalling systems. It is argued that its primary action is to maintain the expression of those signalling components responsible for stabilizing the low resting state of these two signalling pathways. This phenotypic stability role is facilitated through the ability of vitamin D to increase the expression of both Nrf2 and the anti-ageing protein Klotho, which are also major regulators of Ca(2+) and redox signalling. A decline in Vitamin D levels will lead to a decline in the stability of this regulatory signalling network and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca(2+) signalling.
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31
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Refaat B, El-Shemi AG, Kensara OA, Mohamed AM, Idris S, Ahmad J, Khojah A. Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2015. [PMID: 26205949 PMCID: PMC4513788 DOI: 10.1186/s13046-015-0187-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer. Methods Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of β-catenin, transforming growth factor-β1 (TGF-β1), TGF-β type 2 receptor (TGF-βR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, β-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-β1, HSP-90 and COX-2 proteins. Results Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, β-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-β1, TGF-βR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups. Conclusions Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/β-catenin pathway, TGF-β1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.
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Affiliation(s)
- Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia.
| | - Adel Galal El-Shemi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. .,Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Osama Adnan Kensara
- Clinical Nutrition Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia.
| | - Amr Mohamed Mohamed
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia. .,Clinical Laboratory Diagnosis, Department of Animal Medicine, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt.
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia.
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia.
| | - Athar Khojah
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al-Abdeyah, PO Box 7607, Makkah, Kingdom of Saudi Arabia.
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32
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Wierzbicka JM, Binek A, Ahrends T, Nowacka JD, Szydłowska A, Turczyk Ł, Wąsiewicz T, Wierzbicki PM, Sądej R, Tuckey RC, Slominski AT, Chybicki J, Adrych K, Kmieć Z, Żmijewski MA. Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture. Int J Oncol 2015; 47:1084-96. [PMID: 26260259 PMCID: PMC4532196 DOI: 10.3892/ijo.2015.3088] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 06/15/2015] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is an emerging global problem with the rapid increase in its incidence being associated with an unhealthy lifestyle. Epidemiological studies have shown that decreased levels of vitamin D3 significantly increases the risk of CRC. Furthermore, negative effects of vitamin D3 deficiency can be compensated by appropriate supplementation. Vitamin D3 was shown to inhibit growth and induce differentiation of cancer cells, however, excessive vitamin D3 intake leads to hypercalcemia. Thus, development of efficient vitamin D3 analogues with limited impact on calcium homeostasis is an important scientific and clinically relevant task. The aims of the present study were to compare the antiproliferative potential of classic vitamin D3 metabolites (1α,25(OH)2D3 and 25(OH)D3) with selected low calcemic analogues (calcipotriol and 20(OH)D3) on CRC cell lines and to investigate the expression of vitamin D-related genes in CRC cell lines and clinical samples. Vitamin D3 analogues exerted anti-proliferative effects on all CRC cell lines tested. Calcipotriol proved to be as potent as 1α,25(OH)2D3 and had more efficacy than 20-hydroxyvitamin D3. In addition, the analogs tested effectively inhibited the formation of colonies in Matrigel. The expression of genes involved in 1α,25(OH)2D3 signaling and metabolism varied in cell lines analysed, which explains in part their different sensitivities to the various analogues. In CRC biopsies, there was decreased VDR expression in tumor samples in comparison to the surgical margin and healthy colon samples (p<0.01). The present study indicates that vitamin D3 analogues which have low calcemic activity, such as calcipotriol or 20(OH)D3, are very promising candidates for CRC therapy. Moreover, expression profiling of vitamin D-related genes is likely to be a powerful tool in the planning of anticancer therapy. Decreased levels of VDR and increased CYP24A1 expression in clinical samples underline the importance of deregulation of vitamin D pathways in the development of CRC.
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Affiliation(s)
- J M Wierzbicka
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - A Binek
- Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - T Ahrends
- Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - J D Nowacka
- Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - A Szydłowska
- Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - Ł Turczyk
- Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - T Wąsiewicz
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - P M Wierzbicki
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - R Sądej
- Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - R C Tuckey
- School of Chemistry and Biochemistry, The University of Western Australia, Crawley WA, Australia
| | - A T Slominski
- Department of Dermatology, University of Alabama Birmingham, VA Medical Center, Birmingham, AL 35294, USA
| | - J Chybicki
- Department of General Surgery, Hospital Ministry Internal Affairs, 80104 Gdańsk, Poland
| | - K Adrych
- Department of Hepatology and Gastroenterology, Faculty of Medicine, Medical University of Gdańsk, 80210 Gdańsk, Poland
| | - Z Kmieć
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - M A Żmijewski
- Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
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Smolle MA, Pichler M, Haybaeck J, Gerger A. Genetic markers of recurrence in colorectal cancer. Pharmacogenomics 2015; 16:1315-28. [DOI: 10.2217/pgs.15.83] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) worldwide belongs to one of the most frequent cancers affecting both genders. Surgery and 5-fluorouracil-based adjuvant chemotherapy are recommended for patients with high-risk stage II and stage III colon carcinoma. Mutations of genes encoding for specific proteins may have an impact on the time to recurrence. These proteins act over specific signaling pathways, are implicated in metabolic processes and regulate the cell cycle. Though many retrospective studies show strong associations between genetic mutations and the clinical outcome of patients with CRC, currently no validated biomarkers are used in clinical routine settings. Therefore, large prospective validation studies should be carried out in order to strengthen the position of genetic mutations in personalized treatment of patients with CRC.
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Affiliation(s)
- Maria Anna Smolle
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | | | - Armin Gerger
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
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Giammanco M, Di Majo D, La Guardia M, Aiello S, Crescimannno M, Flandina C, Tumminello FM, Leto G. Vitamin D in cancer chemoprevention. PHARMACEUTICAL BIOLOGY 2015; 53:1399-1434. [PMID: 25856702 DOI: 10.3109/13880209.2014.988274] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. OBJECTIVE The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. METHODS A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. RESULTS AND CONCLUSION Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.
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Abstract
Vitamin D and calcium are well-established regulators of keratinocyte proliferation and differentiation. Therefore, it was not a great surprise that deletion of the vitamin D receptor (VDR) should predispose the skin to tumor formation, and that the combination of deleting both the VDR and calcium sensing receptor (CaSR) should be especially pro-oncogenic. In this review I have examined 4 mechanisms that appear to underlie the means by which VDR acts as a tumor suppressor in skin. First, DNA damage repair is curtailed in the absence of the VDR, allowing mutations in DNA to accumulate. Second and third involve the increased activation of the hedgehog and β-catenin pathways in the epidermis in the absence of the VDR, leading to poorly regulated proliferation with reduced differentiation. Finally, VDR deletion leads to a shift in the expression of long noncoding RNAs toward a more oncogenic profile. How these different mechanisms interact and their relative importance in the predisposition of the VDR null epidermis to tumor formation remain under active investigation.
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Affiliation(s)
- Daniel D Bikle
- VA Medical Center and University of California San Francisco, 1700 Owens Street, Room 373, San Francisco, CA 94158, USA
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Wang WB, Yang Y, Zhao YP, Zhang TP, Liao Q, Shu H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World J Gastroenterol 2014; 20:15682-15690. [PMID: 25400452 PMCID: PMC4229533 DOI: 10.3748/wjg.v20.i42.15682] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/04/2014] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
Resistance to 5-fluorouracil (5-FU), an important anticancer drug, is a serious challenge in the treatment of pancreatic cancer. Equilibrative nucleoside transporter 1 and multidrug-resistance protein (MRP) 5 and MRP8, rather than P-glycoprotein, play important roles in 5-FU transport. Thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase and thymidine phosphorylase are four key enzymes involved in 5-FU metabolism. Other metabolic enzymes, including uridine monophosphate synthetase, also contribute to chemoresistance. Intracellular signaling pathways are an integrated network, and nuclear factor kappa-light-chain-enhancer of activated B cells, AKT and extracellular signal-regulated kinases are signaling pathways that are particularly relevant to 5-FU resistance. In addition, recent reports indicate that STAT-3 is a crucial survival protein. Proteomic assays provide a powerful tool for identifying target proteins and understanding the role of microRNAs and stromal factors to facilitate the development of strategies to combat 5-FU resistance.
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Ng K. Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence? CURRENT COLORECTAL CANCER REPORTS 2014; 10:339-345. [PMID: 25221464 DOI: 10.1007/s11888-014-0238-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Vitamin D insufficiency is highly prevalent in the U.S., particularly among colorectal cancer (CRC) patients. These low levels of vitamin D are concerning in light of increasing evidence that vitamin D may have health benefits beyond skeletal outcomes. Prospective observational studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC, and randomized clinical trials are desperately needed to establish causality. Moreover, there remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents. In this review, the available published evidence on vitamin D's activity in CRC will be summarized, spanning preclinical, epidemiological, and clinical studies, and future research directions will be discussed.
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Affiliation(s)
- Kimmie Ng
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, , ,
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Milczarek M, Filip-Psurska B, Swiętnicki W, Kutner A, Wietrzyk J. Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncol Rep 2014; 32:491-504. [PMID: 24919507 PMCID: PMC4091879 DOI: 10.3892/or.2014.3247] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 05/02/2014] [Indexed: 12/31/2022] Open
Abstract
In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.
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Affiliation(s)
- Magdalena Milczarek
- Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Beata Filip-Psurska
- Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | | | - Andrzej Kutner
- Pharmaceutical Research Institute, 01-793 Warsaw, Poland
| | - Joanna Wietrzyk
- Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
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Abstract
The negative association of the latitude where people live and the incidence of non cutaneous cancer in that population in North America have been demonstrated in many studies for many types of cancer. Since the intensity of UVB exposure decreases with increasing latitude, and UVB exposure provides the mechanism for vitamin D production in the skin, the hypothesis that increased vitamin D provides protection against the development of cancer has been proposed. This hypothesis has been tested in a substantial number of prospective and case control studies and in a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development. Most of the studies have focused on colorectal, breast, and prostate cancer. The results have been mixed. The most compelling data for a beneficial relationship between vitamin D intake or serum 25OHD levels and cancer have been obtained for colorectal cancer. The bulk of the evidence also favors a beneficial relationship for breast cancer, but the benefit of vitamin D for prostate and skin cancer in clinical populations has been difficult to demonstrate. RTCs in general have been flawed in execution or too small to provide compelling evidence one way or the other. In contrast, animal studies have been quite consistent in their demonstration that vitamin D and/or its active metabolite 1,25 dihydroxyvitamin D (1,25(OH)2D) can prevent the development and/or treat a variety of cancers in a variety of animal models. Furthermore, 1,25(OH)2D has been shown to impact a number of cellular mechanisms that would be expected to underlie its anticancer effects. Thus, there is a dilemma-animal and cellular studies strongly support a role for vitamin D in the prevention and treatment of cancer, but the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic.
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Affiliation(s)
- Daniel D Bikle
- Endocrine Research Unit, Departments of Medicine and Dermatology, VA Medical Center and University of California San Francisco, 4150 Clement St (111N), San Francisco, CA, 94121, USA,
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Wang WM, Deng JL, Gu XC, Tang YH, Zhang GQ, Zhou Y. ERCC1 and TS expression and prognosis in colon cancer after postoperative adjuvant chemotherapy. Shijie Huaren Xiaohua Zazhi 2014; 22:24-30. [DOI: 10.11569/wcjd.v22.i1.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the relationship between excision repair cross-complementing group 1 (ERCC1) expression, thymidylate synthase (TS) expression and the prognosis in colon cancer after postoperative adjuvant chemotherapy.
METHODS: Seventy-six patients who were diagnosed with colon cancer for the first time were enrolled in our study. All the patients received radical operation, were pathologically diagnosed with stage Ⅱ or Ⅲ disease, accepted FOLFOX4 (L-OHP+5-Fu+CF) chemotherapy and were followed at least 3 years. Immunohistochemistry was used to detect ERCC1 and TS expression levels in colon cancer. The relationship between the expression of ERCC1 and TS and postoperative survival was analyzed retrospectively.
RESULTS: The positive expression rates of ERCC1 and TS in colon cancer were 36.8% and 43.4%, respectively. There were a negative correlation between the positive expression of ERCC1 and TS and tumor differentiation (P = 0.019 and 0.024). The median survival time was significantly longer in patients with negative ERCC1 expression than in those with positive expression (P < 0.05), and in patients with negative TS expression than in those with positive expression (P < 0.05). Cox multivariate regression analysis revealed that patients with positive ERCC1 and TS expression did not benefit from chemotherapy (HR = 3.50, 95%CI: 1.59-7.73, P = 0.002; HR = 0.52, 95%CI: 0.35-0.87, P = 0.010).
CONCLUSION: ERCC1 and TS may be biomarkers for predicting the prognosis of colon cancer patients receiving chemotherapy.
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Singh N, Aslam MN, Varani J, Chakrabarty S. Induction of calcium sensing receptor in human colon cancer cells by calcium, vitamin D and aquamin: Promotion of a more differentiated, less malignant and indolent phenotype. Mol Carcinog 2013; 54:543-53. [PMID: 26076051 DOI: 10.1002/mc.22123] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 11/26/2013] [Indexed: 12/22/2022]
Abstract
The calcium sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor. Cancer cells that do not express CaSR (termed CaSR null) are highly malignant while acquisition of CaSR expression in these cells circumvents the malignant phenotype. We hypothesize that chemopreventive agents mediate their action through the induction of CaSR. Here, we compare the effectiveness of Ca(2+), vitamin D, and Aquamin (a marine algae product containing Ca(2+), magnesium and detectable levels of 72 additional minerals) on the induction of CaSR in the CBS and HCT116 human colon carcinoma cell lines and the corresponding CaSR null cells isolated from these lines. All three agonists induced CaSR mRNA and protein expression and inhibited cellular proliferation in the parental and CaSR null cells. Aquamin was found to be most potent in this regard. Induction of CaSR expression by these agonists resulted in demethylation of the CaSR gene promoter with a concurrent increase in CaSR promoter reporter activity. However, demethylation per se did not induce CaSR transcription. Induction of CaSR expression resulted in a down-regulated expression of tumor inducers and up-regulated expression of tumor suppressors. Again, Aquamin was found to be most potent in these biologic effects. This study provides a rationale for the use of a multi-mineral approach in the chemoprevention of colon cancer and suggests that induction of CaSR may be a measure of the effectiveness of chemopreventive agents.
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Affiliation(s)
- Navneet Singh
- Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois
| | - Muhammad N Aslam
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - James Varani
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Subhas Chakrabarty
- Department of Microbiology, Immunology and Cell Biology Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IIllinois
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Szkandera J, Absenger G, Pichler M, Stotz M, Langsenlehner T, Samonigg H, Renner W, Gerger A. Association of common gene variants in vitamin D modulating genes and colon cancer recurrence. J Cancer Res Clin Oncol 2013; 139:1457-64. [PMID: 23793229 DOI: 10.1007/s00432-013-1461-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 06/14/2013] [Indexed: 12/24/2022]
Abstract
PURPOSE Low concentrations of 25-hydroxyvitamin D3 (25(OH)D) have been associated with increased risk and poor prognosis of various cancer types, including colon cancer. Common genetic variants in genes that influence circulating 25(OH)D levels may affect vitamin D concentrations and risk of vitamin D insufficiency. In the present study, we investigated the association of three functional gene variants in GC (rs2282679 T>G), DHCR7 (rs12785878 G>T) and CYP2R1 (rs10741657 A>G) with time to recurrence (TTR) in patients with stages II and III colon cancer. METHODS Two hundred and sixty-four patients were included in this retrospective study. Genomic DNA was genotyped for GC rs2282679 T>G, DHCR7 rs12785878 G>T and CYP2R1 rs10741657 A>G by 5'-exonuclease (TaqMan™) technology. RESULTS In the univariate analysis, GC rs2282679 GG was significantly associated with decreased TTR (HR = 3.30, 95 % CI 1.09-9.97, p = 0.034) in patients with surgery alone and remained significantly associated in multivariate analysis including lymph node involvement and clinical stage (HR = 3.64, 95 % CI 1.16-11.46, p = 0.027). In patients with adjuvant chemotherapy, GC rs2282679 T>G was not significantly associated with TTR (HR = 1.02, 95 % CI 0.44-2.37, p = 0.964). Furthermore, we observed a trend toward decreased TTR in patients harboring the CYP2R1 rs10741657 A>G gene variant including all patients (HR = 1.50, 95 % CI 0.98-2.28, p = 0.060). No association was found between DHCR7 rs12785878 G>T and TTR in our study cohort. CONCLUSION In conclusion, our results may indicate a prognostic effect of GC rs2282679 in stages II and III colon cancer patients with surgery alone. Larger studies have to be performed to validate our findings.
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Affiliation(s)
- Joanna Szkandera
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
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Padi SK, Zhang Q, Rustum YM, Morrison C, Guo B. MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology 2013; 145:437-46. [PMID: 23619147 PMCID: PMC3722307 DOI: 10.1053/j.gastro.2013.04.012] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 04/08/2013] [Accepted: 04/15/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Vitamin D protects against colorectal cancer through unclear mechanisms. We investigated the effects of calcitriol (1α,25-dihydroxyvitamin D3; the active form of vitamin D) on levels of different microRNAs (miRNAs) in colorectal cancer cells from humans and xenograft tumors in mice. METHODS Expression of miRNAs in colorectal cancer cell lines was examined using the Ambion mirVana miRNA Bioarray. The effects of calcitriol on expression of miR-627 and cell proliferation were determined by real-time polymerase chain reaction and WST-1 assay, respectively; growth of colorectal xenograft tumors was examined in nude mice. Real-time polymerase chain reaction was used to analyze levels of miR-627 in human colon adenocarcinoma samples and nontumor colon mucosa tissues (controls). RESULTS In HT-29 cells, miR-627 was the only miRNA significantly up-regulated by calcitriol. Jumonji domain containing 1A (JMJD1A), which encodes a histone demethylase, was found to be a target of miR-627. By down-regulating JMJD1A, miR-627 increased methylation of histone H3K9 and suppressed expression of proliferative factors, such as growth and differentiation factor 15. Calcitriol induced expression of miR-627, which down-regulated JMJD1A and suppressed growth of xenograft tumors from HCT-116 cells in nude mice. Overexpression of miR-627 prevented proliferation of colorectal cancer cell lines in culture and growth of xenograft tumors in mice. Conversely, blocking the activity of miR-627 inhibited the tumor suppressive effects of calcitriol in cultured colorectal cancer cells and in mice. Levels of miR-627 were decreased in human colon adenocarcinoma samples compared with controls. CONCLUSIONS miR-627 mediates tumor-suppressive epigenetic activities of vitamin D on colorectal cancer cells and xenograft tumors in mice. The messenger RNA that encodes the histone demethylase JMJD1A is a direct target of miR-627. Reagents designed to target JMJD1A or its messenger RNA, or increase the function of miR-627, might have the same antitumor activities of vitamin D without the hypercalcemic side effects.
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Affiliation(s)
- Sathish K.R. Padi
- Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58108
| | - Qunshu Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58108
| | - Youcef M Rustum
- Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | - Carl Morrison
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263
| | - Bin Guo
- Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58108
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Milczarek M, Psurski M, Kutner A, Wietrzyk J. Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model. BMC Cancer 2013; 13:294. [PMID: 23777514 PMCID: PMC3689643 DOI: 10.1186/1471-2407-13-294] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 06/12/2013] [Indexed: 02/08/2023] Open
Abstract
Background Active vitamin D analogs that are less toxic than calcitriol can be useful in the combined treatment of patients suffering from colon cancer. In the present study we demonstrate, for the first time in an in vivo model system, the biological effect of combined therapy using 5-fluorouracil (5-FU) along with vitamin D analog PRI-2191 (tacalcitol, 1,24-dihydroxyvitamin D3) or PRI-2205 (5,6-trans-isomer of calcipotriol) on colon cancer. Methods We investigated the influence of vitamin D analogs on the anticancer activity of 5-FU or capecitabine in the treatment of mice bearing MC38 mouse colon tumors implanted subcutaneously or orthotopically. The cell cycle distribution, E-cadherin expression and caspase 3/7 activity in vitro were also evaluated. Results We observed that both PRI-2191 and PRI-2205 significantly enhanced the antitumor activity of 5-FU; but these results depend on the treatment regimen. Applying the optimal schedule of combined therapy we observed a significant decrease in tumor growth, metastasis and also a prolongation of the survival time of mice, in comparison with the administrations of 5-FU given alone. Both combinations indicated a synergistic effect and did not cause toxicity. Moreover, analogs applied after completed course of administration of 5-FU, prolonged the antitumor effect of the drug. Furthermore, when the prodrug of 5-FU, capecitabine, was used, potentiation of its activity was also observed. Conclusions Our data suggest that vitamin D analogs (especially PRI-2191) might be potentially applied to clinical use in order to enhance the anticancer effect of 5-FU and also prolong its activity against colon cancer. The activity of PRI-2191 is realized through stopping the cells in the G0/G1 cell cycle phase and increasing the expression of E-cadherin.
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Affiliation(s)
- Magdalena Milczarek
- Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla St. 12, Wroclaw 53-114, Poland
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Singh N, Chakrabarty S. Induction of CaSR expression circumvents the molecular features of malignant CaSR null colon cancer cells. Int J Cancer 2013; 133:2307-14. [PMID: 23674327 DOI: 10.1002/ijc.28270] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 04/29/2013] [Indexed: 12/16/2022]
Abstract
We recently reported on the isolation and characterization of calcium sensing receptor (CaSR) null human colon cancer cells (Singh et al., Int J Cancer 2013; 132: 1996-2005). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis.
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Affiliation(s)
- Navneet Singh
- Department of Microbiology, Immunology and Cell Biology, Simmons Cancer Institute, Southern Illinois University, School of Medicine, Springfield, IL
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Singh N, Promkan M, Liu G, Varani J, Chakrabarty S. Role of calcium sensing receptor (CaSR) in tumorigenesis. Best Pract Res Clin Endocrinol Metab 2013; 27:455-63. [PMID: 23856272 DOI: 10.1016/j.beem.2013.04.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The extracellular Ca(2+)-sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor in colon cancer. CaSR mediates its biologic effects through diverse mechanisms. Loss of CaSR expression activates a myriad of stem cell-like molecular features that drive and sustain the malignant and drug-resistant phenotypes of colon cancer. This CaSR-null phenotype, however, is not irreversible and induction of CaSR expression in CaSR-null cells promotes cell death mechanisms and restores drug sensitivity. The CaSR also functions as a tumor suppressor in breast cancer and promotes cellular sensitivity to cytotoxic drugs. BRCA1 and CaSR functions intersect in breast cancer cells, and CaSR activation can rescue breast cancer cells from the deleterious effect of BRCA1 mutations.
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Affiliation(s)
- Navneet Singh
- Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology and Simmons Cancer Institute, Springfield, IL, USA.
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Kósa JP, Horváth P, Wölfling J, Kovács D, Balla B, Mátyus P, Horváth E, Speer G, Takács I, Nagy Z, Horváth H, Lakatos P. CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells. World J Gastroenterol 2013; 19:2621-8. [PMID: 23674869 PMCID: PMC3645380 DOI: 10.3748/wjg.v19.i17.2621] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 08/21/2012] [Accepted: 08/25/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity.
METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by real-time reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity.
RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1-inhibiting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation.
CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.
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Cellular responses to TGFβ and TGFβ receptor expression in human colonic epithelial cells require CaSR expression and function. Cell Calcium 2013; 53:366-71. [PMID: 23639611 DOI: 10.1016/j.ceca.2013.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 03/11/2013] [Accepted: 04/08/2013] [Indexed: 11/20/2022]
Abstract
CaSR and TGFβ are robust promoters of differentiation in the colonic epithelium. Loss of cellular responses to TGFβ or loss of CaSR expression is tightly linked to malignant progression. Human colonic epithelial CBS cells, originally developed from a differentiated human colon tumor, retain CaSR expression and function, TGFβ responsiveness and TGFβ receptor expression. Thus, these cells offer a unique opportunity in determining the functional linkage (if any) between CaSR and TGFβ. Knocking down CaSR expression abrogated TGFβ-mediated cellular responses and attenuated the expression of TGFβ receptors. Ca²⁺ or vitamin D treatment induced CaSR expression with a concurrent up-regulation of TGFβ receptor expression. Ca²⁺ or vitamin D, however, did not induce CaSR in CaSR knocked down cells and without CaSR; there was no up-regulation of TGFβ receptor. It is concluded that TGFβ receptor expression and TGFβ mediated responses requires CaSR expression and function.
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Calcium sensing receptor signalling in physiology and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2012; 1833:1732-44. [PMID: 23267858 DOI: 10.1016/j.bbamcr.2012.12.011] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 12/10/2012] [Accepted: 12/12/2012] [Indexed: 12/13/2022]
Abstract
The calcium sensing receptor (CaSR) is a class C G-protein-coupled receptor that is crucial for the feedback regulation of extracellular free ionised calcium homeostasis. While extracellular calcium (Ca(2+)o) is considered the primary physiological ligand, the CaSR is activated physiologically by a plethora of molecules including polyamines and l-amino acids. Activation of the CaSR by different ligands has the ability to stabilise unique conformations of the receptor, which may lead to preferential coupling of different G proteins; a phenomenon termed 'ligand-biased signalling'. While mutations of the CaSR are currently not linked with any malignancies, altered CaSR expression and function are associated with cancer progression. Interestingly, the CaSR appears to act both as a tumour suppressor and an oncogene, depending on the pathophysiology involved. Reduced expression of the CaSR occurs in both parathyroid and colon cancers, leading to loss of the growth suppressing effect of high Ca(2+)o. On the other hand, activation of the CaSR might facilitate metastasis to bone in breast and prostate cancer. A deeper understanding of the mechanisms driving CaSR signalling in different tissues, aided by a systems biology approach, will be instrumental in developing novel drugs that target the CaSR or its ligands in cancer. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
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