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Matos ALSA, Ovens AJ, Jakobsen E, Iglesias-Gato D, Bech JM, Friis S, Bak LK, Madsen GI, Oakhill JS, Puustinen P, Moreira JMA. Salicylate-Elicited Activation of AMP-Activated Protein Kinase Directly Triggers Degradation of C-Myc in Colorectal Cancer Cells. Cells 2025; 14:294. [PMID: 39996767 PMCID: PMC11854256 DOI: 10.3390/cells14040294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/03/2024] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
Abstract
Aspirin has consistently shown preventive effects in some solid cancers, notably colorectal cancer. However, the precise molecular mechanisms underlying this positive effect have remained elusive. In this study, we used an azoxymethane-induced mouse model of colon carcinogenesis to identify aspirin-associated molecular alterations that could account for its cancer-preventive effect. Transcriptomic analysis of aspirin-treated mice showed a strong reduction in c-Myc protein levels and effects on the Myc-dependent transcriptional program in colonic cells. Proto-oncogene c-Myc cooperates with AMP-activated protein kinase (AMPK) to control cellular energetics. Here, we show that salicylate, the active metabolite of aspirin, reduces c-Myc protein expression levels through multiple mechanisms that are both AMPK dependent and independent. This effect is cell-type dependent and occurs at both the transcriptional and post-translational levels. Salicylate-induced AMPK activation leads to the phosphorylation of c-Myc at Thr400, as well as its destabilization and degradation. Our results reveal a complex, multilayered, negative effect of salicylate on c-Myc protein abundance and suggest that chronic depletion of c-Myc can counteract the neoplastic transformation of colorectal epithelium, underpinning the preventive effect of aspirin on colorectal cancer.
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Affiliation(s)
- Ana Laura S. A. Matos
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil
| | - Ashley J. Ovens
- Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia (J.S.O.)
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
| | - Emil Jakobsen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Diego Iglesias-Gato
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Jacob M. Bech
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Sino-Danish Center for Education and Research, Aarhus University, 8000 Aarhus, Denmark
| | - Stine Friis
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Lasse Kristoffer Bak
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, 2600 Glostrup, Denmark
- Translational Research Center (TRACE), Copenhagen University Hospital-Rigshospitalet, 2600 Glostrup, Denmark
| | - Gunvor I. Madsen
- Department of Pathology, Odense University Hospital, 5000 Odense, Denmark
| | - Jonathan S. Oakhill
- Metabolic Signalling Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC 3065, Australia (J.S.O.)
- Department of Medicine, University of Melbourne, Parkville, VIC 3010, Australia
| | - Pietri Puustinen
- Cell Death and Metabolism, Danish Cancer Society Research Center (DCRC), 2100 Copenhagen, Denmark
| | - José M. A. Moreira
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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Buckland GR, Wilding SA, McDonnell D, Hamady ZZR. The role of aspirin in the prevention of pancreatic cancer: A nested case-control study in the UK Biobank. Pancreatology 2024; 24:947-953. [PMID: 39155166 DOI: 10.1016/j.pan.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/21/2024] [Accepted: 08/09/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) usage has been associated with pancreatic ductal adenocarcinoma (PDAC) prevention, though epidemiological data have not reliably demonstrated this. The aim of this study is to identify if aspirin and other NSAIDs are effective in the primary prevention of PDAC in a large UK prospective cohort. METHODS A nested case-control study was conducted using the UK Biobank cohort. Incident PDAC cases (n = 1129 of whom 239 (21.2 %) were using aspirin) were age and sex-matched with cancer-free controls (n = 8822 of whom 1752 (19.9 %) were using aspirin). Conditional logistic regression models were used to generate odds ratios (ORs) and 95 % confidence intervals (CI) for risk of PDAC with and without regular use of aspirin, non-aspirin NSAIDs and all NSAIDs respectively. Exploratory analyses were carried out assessing interactions with diabetes mellitus (DM) as a condition with increased pancreatic cancer risk. RESULTS Regular aspirin use at initial recruitment was independently associated with a decreased risk of PDAC (OR [95 % CI] = 0.80 [0.68-0.95] P = 0.01). Regular non-aspirin NSAID use was not associated with a risk reduction of PDAC (OR [95 % CI] = 1.01 [0.84-1.23] P = 0.88). Exploratory analyses showed that in those with DM; regular aspirin use reduced risk of PDAC (OR [95 % CI] = 0.60 [0.42-0.85] P = 0.004) compared to non-use. DISCUSSION Regular aspirin use is associated with a reduction in risk of PDAC. The reduced risk is more apparent in participants with DM.
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Affiliation(s)
- George R Buckland
- University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK
| | - Sam A Wilding
- Southampton Clinical Trials Unit, University of Southampton, UK
| | - Declan McDonnell
- University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK; Faculty of Medicine, Human Development and Health, University of Southampton, UK
| | - Zaed Z R Hamady
- University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK; Faculty of Medicine, Human Development and Health, University of Southampton, UK.
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Li X, Meng Z, Hua Y, Li Z, Yin B, Qian B, Yu H, Li Z, Zhou Y, Feng Z, Lu S, Ke S, Bai M, Fu Y, Ma Y. Identification and validation of ferroptosis-related hub genes and immune infiltration in liver ischemia-reperfusion injury. Genomics 2024; 116:110918. [PMID: 39147333 DOI: 10.1016/j.ygeno.2024.110918] [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: 03/14/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
Ischemia-reperfusion injury (IRI) is a cumulation of pathophysiological processes that involves cell and organelle damage upon blood flow constraint and subsequent restoration. However, studies on overall immune infiltration and ferroptosis in liver ischemia-reperfusion injury (LIRI) are limited. This study explored immune cell infiltration and ferroptosis in LIRI using bioinformatics and experimental validation. The GSE151648 dataset, including 40 matched pairs of pre- and post- transplant liver samples was downloaded for bioinformatic analysis. Eleven hub genes were identified by overlapping differentially expressed genes (DEGs), iron genes, and genes identified through weighted gene co-expression network analysis (WGCNA). Subsequently, the pathway enrichment, transcription factor-target, microRNA-mRNA and protein-protein interaction networks were investigated. The diagnostic model was established by logistic regression, which was validated in the GSE23649 and GSE100155 datasets and verified using cytological experiments. Moreover, several drugs targeting these genes were found in DrugBank, providing a more effective treatment for LIRI. In addition, the expression of 11 hub genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR) in liver transplantation samples and animal models. The expression of the 11 hub genes increased in LIRI compared with the control. Five genes were significantly enriched in six biological process terms, six genes showed high enrichment for LIRI-related signaling pathways. There were 56 relevant transcriptional factors and two central modules in the protein-protein interaction network. Further immune infiltration analysis indicated that immune cells including neutrophils and natural killer cells were differentially accumulated in the pre- and post-transplant groups, and this was accompanied by changes in immune-related factors. Finally, 10 targeted drugs were screened. Through bioinformatics and further experimental verification, we identified hub genes related to ferroptosis that could be used as potential targets to alleviate LIRI.
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Affiliation(s)
- Xinglong Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhanzhi Meng
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongliang Hua
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zihao Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Yin
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baolin Qian
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongjun Yu
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhongyu Li
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongzhi Zhou
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhigang Feng
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; The First Department of General Surgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China
| | - Shounan Lu
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shanjia Ke
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Miaoyu Bai
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yao Fu
- Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yong Ma
- Department of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Ding K, Zhangwang J, Lei M, Xiong C. Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets. BMC Genomics 2024; 25:231. [PMID: 38431573 PMCID: PMC10909270 DOI: 10.1186/s12864-024-10116-5] [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: 01/04/2024] [Accepted: 02/13/2024] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. METHODS Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. RESULTS After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). CONCLUSION Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.
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Affiliation(s)
- Kaixi Ding
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Juejue Zhangwang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Ming Lei
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
| | - Chunping Xiong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
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Pandey M, Rajput M, Singh P, Shukla M, Zhu B, Koshiol J. Aspirin and Cancer Survival: An Analysis of Molecular Mechanisms. Cancers (Basel) 2024; 16:223. [PMID: 38201650 PMCID: PMC10778469 DOI: 10.3390/cancers16010223] [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: 10/07/2023] [Revised: 12/25/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
The benefit of aspirin on cancer survival is debated. Data from randomized clinical trials and cohort studies are discordant, although a meta-analysis shows a clear survival advantage when aspirin is added to the standard of care. However, the mechanism by which aspirin improves cancer survival is not clear. A PubMed search was carried out to identify articles reporting genes and pathways that are associated with aspirin and cancer survival. Gene ontology and pathway enrichment analysis was carried out using web-based tools. Gene-gene and protein-protein interactions were evaluated. Crosstalk between pathways was identified and plotted. Forty-one genes were identified and classified into primary genes (PTGS2 and PTGES2), genes regulating cellular proliferation, interleukin and cytokine genes, and DNA repair genes. The network analysis showed a rich gene-gene and protein-protein interaction between these genes and proteins. Pathway enrichment showed the interleukin and cellular transduction pathways as the main pathways involved in aspirin-related survival, in addition to DNA repair, autophagy, extracellular matrix, and apoptosis pathways. Crosstalk of PTGS2 with EGFR, JAK/AKT, TP53, interleukin/TNFα/NFκB, GSK3B/BRCA/PARP, CXCR/MUC1, and WNT/CTNNB pathways was identified. The results of the present study demonstrate that aspirin improves cancer survival by the interplay of 41 genes through a complex mechanism. PTGS2 is the primary target of aspirin and impacts cancer survival through six primary pathways: the interleukin pathway, extracellular matrix pathway, signal transduction pathway, apoptosis pathway, autophagy pathway, and DNA repair pathway.
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Affiliation(s)
- Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India; (M.R.)
| | - Monika Rajput
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India; (M.R.)
| | - Pooja Singh
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India; (M.R.)
| | - Mridula Shukla
- RRL, Dr. Lalpath Labs Ltd., Shivpur, Varanasi 221003, India
| | - Bin Zhu
- Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), National Institutes of Health (NIH), 9609 Medical Center Drive, RM 6-E212, Rockville, MD 20850, USA (J.K.)
| | - Jill Koshiol
- Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), National Institutes of Health (NIH), 9609 Medical Center Drive, RM 6-E212, Rockville, MD 20850, USA (J.K.)
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Mohamed-Ezzat RA, Srour AM. Design and Synthesis of Aspirin-chalcone Mimic Conjugates as Potential Anticancer Agents. Anticancer Agents Med Chem 2024; 24:544-557. [PMID: 38204260 DOI: 10.2174/0118715206280025231213065519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND Extensive research has been conducted on aspirin, a widely recognized NSAID medication, regarding its potential as an anticancer agent. Studies have revealed its ability to trigger cell death in different types of cancer cells. METHODS A set of aspirin-chalcone mimic conjugates 5a-k and 6a-d utilizing the freshly prepared acid chloride of aspirin moiety has been designed and synthesized. To evaluate the newly developed compounds, the NCI 60- cell line panel was employed to assess their anti-proliferative properties. Subsequently, cell cycle analysis was conducted along with an examination of the compounds' impact on the levels of p53, Bax, Bcl-2, active caspase- 3, and their inhibition mechanism of tubulin polymerization. RESULTS Derivative 6c displayed the best anticancer activity among the tested series while 6d was the best against breast cancer MDA-MB-468, therefore both of them were selected for the 5-dose stage, however, targeting MDA-MB-468, PI-flow cytometry of compound 6d proved the triggered cell growth arrest at the G1/S phase avoiding the mitotic cycle in MDA-MB-468 cells. Similarly, the upregulation of oncogenic parameters such as caspase-3, p53, and Bax/Bcl-2, along with the inhibition of PARP-1 enzyme level, was observed with compound 6d. This compound also exhibited a significant ability to induce apoptosis and disrupt the intracellular microtubule network through a promising activity as a tubulin polymerization inhibitor with IC50 = 1.065 ± 0.024 ng/ml. Furthermore, to examine the manner in which compound 6d binds to the active pocket of the tubulin polymerization enzyme, a molecular docking study was conducted. CONCLUSION The study indicated that compound 6d could be a powerful microtubule-destabilizing agent. Therefore, further research on 6d could be worthwhile.
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Affiliation(s)
- Reham A Mohamed-Ezzat
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt
| | - Aladdin M Srour
- Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Cairo, 12622, Egypt
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Liu C, Rokavec M, Huang Z, Hermeking H. Salicylate induces AMPK and inhibits c-MYC to activate a NRF2/ARE/miR-34a/b/c cascade resulting in suppression of colorectal cancer metastasis. Cell Death Dis 2023; 14:707. [PMID: 37898661 PMCID: PMC10613307 DOI: 10.1038/s41419-023-06226-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 10/30/2023]
Abstract
Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not completely understood. Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs. In addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK. The suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53.
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Affiliation(s)
- Chunfeng Liu
- Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany
| | - Matjaz Rokavec
- Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany
| | - Zekai Huang
- Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany
| | - Heiko Hermeking
- Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany.
- German Cancer Consortium (DKTK), Partner site Munich, D-80336, Munich, Germany.
- German Cancer Research Center (DKFZ), D-69210, Heidelberg, Germany.
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Fijałkowski Ł, Skubiszewska M, Grześk G, Koech FK, Nowaczyk A. Acetylsalicylic Acid-Primus Inter Pares in Pharmacology. Molecules 2022; 27:8412. [PMID: 36500502 PMCID: PMC9738180 DOI: 10.3390/molecules27238412] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/24/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Acetylsalicylic acid (ASA) is one of the first drugs to be obtained by synthesis while being the most used. It has experienced the longest lasting commercial success and is considered the most popular drug of the modern era. ASA, originally used as an anti-inflammatory medication, nowadays is predominantly used as an antiplatelet agent for prophylaxis in cardiac patients. Many studies show that the benefits of using ASA far outweigh the potential risk of side effects. With particular emphasis on the possibility of ASA repositioning for new therapies, extending the indications for use beyond the diseases from the spectrum of atherosclerotic diseases, such as cancer, requires shifting the benefit-risk ratio, although very good, even more towards safety. Interesting activities consisting not only of changing the formulation but also modifying the drug molecule seem to be an important goal of the 21st century. ASA has become a milestone in two important fields: pharmacy and medicine. For a pharmacist, ASA is a long-used drug for which individual indications are practically maintained. For a doctor, acetylsalicylic acid is primarily an antiplatelet drug that saves millions of lives of patients with coronary heart disease or after a stroke. These facts do not exempt us from improving therapeutic methods based on ASA, the main goal of which is to reduce the risk of side effects, as well as to extend effectiveness. Modified acetylsalicylic acid molecules already seem to be a promising therapeutic option.
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Affiliation(s)
- Łukasz Fijałkowski
- Department of Pharmacometrics and Molecular Modeling, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland
| | - Magdalena Skubiszewska
- Department of Pharmacometrics and Molecular Modeling, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland
| | - Grzegorz Grześk
- Department of Cardiology and Clinical Pharmacology, Faculty of Health Sciences, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 75 Ujejskiego St., 85-168 Bydgoszcz, Poland
| | | | - Alicja Nowaczyk
- Department of Pharmacometrics and Molecular Modeling, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland
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Vukovic M, Lazarevic M, Mitic D, Jaksic Karisik M, Ilic B, Andric M, Jevtic B, Roganovic J, Milasin J. Acetylsalicylic-acid (ASA) regulation of osteo/odontogenic differentiation and proliferation of human dental pulp stem cells (DPSCs) in vitro. Arch Oral Biol 2022; 144:105564. [PMID: 36215814 DOI: 10.1016/j.archoralbio.2022.105564] [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: 06/13/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVE The study aimed to investigate acetylsalicylic acid (ASA) effects on osteo/odontogenic differentiation and proliferation of dental pulp stem cells (DPSCs) in vitro and the potential involvement of adenosine monophosphate-activated protein kinase (AMPK) pathway in these processes. DESIGN DPSCs were isolated from third molars pulp tissues of five patients and grown in osteogenic medium alone or supplemented with ASA. Expression of DPSCs markers was tested by flow-cytometry. Cytotoxicity of ASA at concentrations of 10, 50 and 100 µg/ml was tested by MTT and NR assays. Osteo/odontogenic differentiation was analyzed via alizarin red staining and ALP activity. Quantitative PCR (qPCR) was used for osteo/odontogenic markers' (DSPP, BMP2, BMP4, BSP, OCN and RUNX2) and c-Myc expression analysis. AMPK inhibition of ASA-induced osteo/odontogenesis was tested by qPCR of selected markers (DSPP, OCN and RUNX2). RESULTS Cytotoxicity assays showed that only the highest ASA dose decreased cell viability (89.1 %). The smallest concentration of ASA applied on DPSCs resulted in a remarkable enhancement of osteo/odontogenic differentiation, as judged by increased mineralized nodules' formation, ALP activity and gene expression of analyzed markers (increase between 2 and 30 folds), compared to untreated cells. ASA also increased DPSCs proliferation. Interestingly, AMPK inhibition per se upregulated DSPP, OCN and RUNX2; the gene upregulation was higher when ASA treatment was also included. c-Myc expression level decreased in cultures treated with ASA, indicating undergoing differentiation processes. CONCLUSIONS Low concentrations of ASA (corresponding to the standard use in cardiovascular patients), were shown to stimulate osteo/odontogenic differentiation of dental pulp stem cells.
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Affiliation(s)
- Mladen Vukovic
- Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia
| | - Milos Lazarevic
- Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia
| | - Dijana Mitic
- Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia
| | - Milica Jaksic Karisik
- Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia
| | - Branislav Ilic
- Clinic for Oral Surgery, School of Dental Medicine, University of Belgrade, Serbia
| | - Miroslav Andric
- Clinic for Oral Surgery, School of Dental Medicine, University of Belgrade, Serbia
| | - Bojan Jevtic
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Serbia
| | - Jelena Roganovic
- Department of Pharmacology in Dentistry, School of Dental Medicine, University of Belgrade, Serbia
| | - Jelena Milasin
- Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia.
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10
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Sidhu H, Capalash N. Synergistic anti-cancer action of salicylic acid and cisplatin on HeLa cells elucidated by network pharmacology and in vitro analysis. Life Sci 2021; 282:119802. [PMID: 34237314 DOI: 10.1016/j.lfs.2021.119802] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/13/2021] [Accepted: 06/30/2021] [Indexed: 01/20/2023]
Abstract
AIM To investigate the anti-cancer potential of salicylic acid and cisplatin combination in HeLa cells and the underlying mechanism. MAIN METHODS Drugs and disease targets were extracted from DrugBank, BATMAN-TCM, STITCH, PharmMapper and Comparative Toxigenomics Database. Cytoscape 3.8.2 was used to merge the protein-protein interaction networks and select core targets. GO and KEGG analysis was done using Metascape and WebGestalt. Effect of salicylic acid and cisplatin alone and in combination on cells viability was studied by MTT assay. The type of interaction between salicylic acid and cisplatin was determined by CompuSyn. Apoptosis was evaluated by molecular docking, Rhodamine-123, DAPI, AO/EtBr staining, flow cytometry, qRT-PCR and western blotting. Metastasis was studied using scratch assay and western blotting. UHRF1 transient silencing was performed by siRNA. KEY FINDINGS Out of 420, 1863 and 1362 respective targets of salicylic acid, cisplatin and cervical cancer, 18 core proteins were enriched in apoptosis and cell migration related pathways. IC50 value of cisplatin was reduced by 14 fold in combination with salicylic acid at IC20 (4 μM). There was loss of mitochondrial membrane potential and downregulation of UHRF1, pAkt, full length PARP and pro-caspase 3 expression. Transient silencing of UHRF1 also induced mitochondrial depolarization and apoptosis. The combination also exhibited anti-metastasis effect as it suppressed migration, upregulated PAX1 and downregulated MMP-2. SIGNIFICANCE Reduction in cisplatin concentration, enhanced anti-cancer effects and UHRF1 downregulation due to synergistic interaction between salicylic acid and cisplatin underscores the therapeutic importance of the combination to overcome chemo-resistance and side effects of cisplatin.
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Affiliation(s)
- Harsimran Sidhu
- Department of Biotechnology, Panjab University, Chandigarh 160014, India
| | - Neena Capalash
- Department of Biotechnology, Panjab University, Chandigarh 160014, India.
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11
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Celebioglu HU. Effects of potential synbiotic interaction between Lactobacillus rhamnosus GG and salicylic acid on human colon and prostate cancer cells. Arch Microbiol 2021; 203:1221-1229. [PMID: 33620523 DOI: 10.1007/s00203-021-02200-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/03/2021] [Accepted: 02/08/2021] [Indexed: 12/11/2022]
Abstract
Salicylic acid, widely distributed in the whole plant kingdom, is a benzoic acid derivative acting as a signal substance in plants, but could be related to differences in cancer incidence, as many herbs and spices contain high amounts. Lactobacillus rhamnosus GG (LGG) is one of the best-known lactic acid bacteria that has been studied for over 30 years. Probiotic and/or commensal bacteria of the human microbiota are known to respond to diet constituents. Therefore, the present study aims at investigating the possible effects of salicylic acid on the probiotic properties of LGG, and in vitro cytotoxic effects of combination of salicylic acid and LGG on human colon and prostate cancer cells. Salicylic acid significantly (p < 0.05) increased co-aggregation of LGG with E. coli (~ twofold) and anti-oxidant properties. Furthermore, it also induced the cytotoxic effects of LGG against human colon cancer cells. These results suggest that interaction of LGG with salicylic acid can exert more probiotic properties.
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12
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Jiang Y, Fang Z, Leonard W, Zhang P. Phenolic compounds in Lycium berry: Composition, health benefits and industrial applications. J Funct Foods 2021. [DOI: 10.1016/j.jff.2020.104340] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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13
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Sankaranarayanan R, Kumar DR, Altinoz MA, Bhat GJ. Mechanisms of Colorectal Cancer Prevention by Aspirin-A Literature Review and Perspective on the Role of COX-Dependent and -Independent Pathways. Int J Mol Sci 2020; 21:ijms21239018. [PMID: 33260951 PMCID: PMC7729916 DOI: 10.3390/ijms21239018] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
Aspirin, synthesized and marketed in 1897 by Bayer, is one of the most widely used drugs in the world. It has a well-recognized role in decreasing inflammation, pain and fever, and in the prevention of thrombotic cardiovascular diseases. Its anti-inflammatory and cardio-protective actions have been well studied and occur through inhibition of cyclooxygenases (COX). Interestingly, a vast amount of epidemiological, preclinical and clinical studies have revealed aspirin as a promising chemopreventive agent, particularly against colorectal cancers (CRC); however, the primary mechanism by which it decreases the occurrences of CRC has still not been established. Numerous mechanisms have been proposed for aspirin’s chemopreventive properties among which the inhibition of COX enzymes has been widely discussed. Despite the wide attention COX-inhibition has received as the most probable mechanism of cancer prevention by aspirin, it is clear that aspirin targets many other proteins and pathways, suggesting that these extra-COX targets may also be equally important in preventing CRC. In this review, we discuss the COX-dependent and -independent pathways described in literature for aspirin’s anti-cancer effects and highlight the strengths and limitations of the proposed mechanisms. Additionally, we emphasize the potential role of the metabolites of aspirin and salicylic acid (generated in the gut through microbial biotransformation) in contributing to aspirin’s chemopreventive actions. We suggest that the preferential chemopreventive effect of aspirin against CRC may be related to direct exposure of aspirin/salicylic acid or its metabolites to the colorectal tissues. Future investigations should shed light on the role of aspirin, its metabolites and the role of the gut microbiota in cancer prevention against CRC.
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Affiliation(s)
- Ranjini Sankaranarayanan
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA;
| | - D. Ramesh Kumar
- Department of Entomology, University of Kentucky, Lexington, KY 40506, USA;
| | - Meric A. Altinoz
- Department of Biochemistry, Acibadem M.A.A. University, Istanbul, Turkey;
| | - G. Jayarama Bhat
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA;
- Correspondence: ; Tel.: +1-605-688-6894
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14
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Acetylsalicylic acid and salicylic acid present anticancer properties against melanoma by promoting nitric oxide-dependent endoplasmic reticulum stress and apoptosis. Sci Rep 2020; 10:19617. [PMID: 33184378 PMCID: PMC7665072 DOI: 10.1038/s41598-020-76824-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Melanoma is the most aggressive and fatal type of skin cancer due to being highly proliferative. Acetylsalicylic acid (ASA; Aspirin) and salicylic acid (SA) are ancient drugs with multiple applications in medicine. Here, we showed that ASA and SA present anticancer effects against a murine model of implanted melanoma. These effects were also validated in 3D- and 2D-cultured melanoma B16F10 cells, where the drugs promoted pro-apoptotic effects. In both in vivo and in vitro models, SA and ASA triggered endoplasmic reticulum (ER) stress, which culminates with the upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). These effects are initiated by ASA/SA-triggered Akt/mTOR/AMPK-dependent activation of nitric oxide synthase 3 (eNOS), which increases nitric oxide and reactive oxygen species production inducing ER stress response. In the end, we propose that ASA and SA instigate anticancer effects by a novel mechanism, the activation of ER stress.
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15
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Sathisaran I, Devidas Bhatia D, Vishvanath Dalvi S. New curcumin-trimesic acid cocrystal and anti-invasion activity of curcumin multicomponent solids against 3D tumor models. Int J Pharm 2020; 587:119667. [PMID: 32702448 DOI: 10.1016/j.ijpharm.2020.119667] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/28/2020] [Accepted: 07/15/2020] [Indexed: 12/25/2022]
Abstract
Curcumin (CUR) is a Biopharmaceutics Classification System (BCS) class IV drug with poor aqueous solubility and low permeability. The dissolution of CUR can be enhanced through the cocrystallization approach. In this work, we report a new cocrystal phase of CUR with trimesic acid (TMA) with the enhanced dissolution of CUR. Cytotoxicity and cell invasion assays were conducted on (2D) monolayers and three-dimensional (3D) tumor models of triple-negative breast cancer (TNBC) cells, MDA-MB-231 using the new CUR-TMA cocrystal phase along with different CUR solid forms prepared in our previous works. The cytotoxicity and internalization assays conducted on 2D monolayers indicated that all CUR multicomponent solid forms except Curcumin-Folic Acid Dihydrate (CUR-FAD) (1:1) coamorphous solid exhibited enhanced bioavailability than unprocessed CUR. Cell invasion assay conducted on 3D tumor spheroid models showed that Curcumin-Hydroxyquinol (CUR-HXQ) cocrystal completely inhibited cell invasion whereas CUR-FAD (1:1) coamorphous solid induced enhanced invasion of cells from spheroid models.
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Affiliation(s)
- Indumathi Sathisaran
- Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355, India
| | - Dhiraj Devidas Bhatia
- Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355, India
| | - Sameer Vishvanath Dalvi
- Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat 382355, India.
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16
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Giampieri R, Cantini L, Giglio E, Bittoni A, Lanese A, Crocetti S, Pecci F, Copparoni C, Meletani T, Lenci E, Lupi A, Baleani MG, Berardi R. Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing. Cancers (Basel) 2020; 12:2724. [PMID: 32977434 PMCID: PMC7598185 DOI: 10.3390/cancers12102724] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/15/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023] Open
Abstract
Colorectal cancer is characterized by high incidence worldwide. Despite increased awareness and early diagnosis thanks to screening programmes, mortality remains high, particularly for patients with metastatic involvement. Immune checkpoint inhibitors or poly (ADP-ribose) polymerase (PARP)-inhibitors have met with disappointing results when used in this setting, opposed to other malignancies. New drugs with different mechanisms of action are needed in this disease. Drug repurposing might offer new therapeutic options, as patients with metastatic colorectal cancer often share risk factors for other chronic diseases and thus frequently are on incidental therapy with these drugs. The aim of this review is to summarise the published results of the activity of drugs used to treat chronic medications in patients affected by colorectal cancer. We focused on antihypertensive drugs, Non-Steroid Anti-inflammatory Drugs (NSAIDs), metformin, antidepressants, statins and antibacterial antibiotics. Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect. It is hoped that further prospective trials that take into account the role of these drugs as anticancer medications are conducted.
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Affiliation(s)
- Riccardo Giampieri
- Division of Medical Oncology, University Hospital—Marche Polytechnic University, Ancona, 60126 Marche, Italy; (L.C.); (E.G.); (A.B.); (A.L.); (S.C.); (F.P.); (C.C.); (T.M.); (E.L.); (A.L.); (M.G.B.); (R.B.)
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17
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Fermented curly kale as a new source of gentisic and salicylic acids with antitumor potential. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103866] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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18
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Sankaranarayanan R, Valiveti CK, Dachineni R, Kumar DR, Lick T, Bhat GJ. Aspirin metabolites 2,3‑DHBA and 2,5‑DHBA inhibit cancer cell growth: Implications in colorectal cancer prevention. Mol Med Rep 2019; 21:20-34. [PMID: 31746356 PMCID: PMC6896348 DOI: 10.3892/mmr.2019.10822] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/08/2019] [Indexed: 12/21/2022] Open
Abstract
Although compelling evidence exists on the ability of aspirin to treat colorectal cancer (CRC), and numerous theories and targets have been proposed, a consensus has not been reached regarding its mechanism of action. In this regard, a relatively unexplored area is the role played by aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA) in its chemopreventive actions. In a previous study, we demonstrated that 2,3-DHBA and 2,5-DHBA inhibited CDK1 enzyme activity in vitro. The aim of the present study was to understand the effect of these metabolites on the enzyme activity of all CDKs involved in cell cycle regulation (CDKs 1, 2, 4 and 6) as well as their effect on clonal formation in three different cancer cell lines. Additionally, in silico studies were performed to determine the potential sites of interactions of 2,3-DHBA and 2,5-DHBA with CDKs. We demonstrated that 2,3-DHBA and 2,5-DHBA inhibits CDK-1 enzyme activity beginning at 500 µM, while CDK2 and CDK4 activity was inhibited only at higher concentrations (>750 µM). 2,3-DHBA inhibited CDK6 enzyme activity from 250 µM, while 2,5-DHBA inhibited its activity >750 µM. Colony formation assays showed that 2,5-DHBA was highly effective in inhibiting clonal formation in HCT-116 and HT-29 CRC cell lines (250–500 µM), and in the MDA-MB-231 breast cancer cell line (~100 µM). In contrast 2,3-DHBA was effective only in MDA-MB-231 cells (~500 µM). Both aspirin and salicylic acid failed to inhibit all four CDKs and colony formation. Based on the present results, it is suggested that 2,3-DHBA and 2,5-DHBA may contribute to the chemopreventive properties of aspirin, possibly through the inhibition of CDKs. The present data and the proposed mechanisms should open new areas for future investigations.
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Affiliation(s)
- Ranjini Sankaranarayanan
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, Avera Health and Sciences Center, South Dakota State University, Brookings, SD 57007, USA
| | - Chaitanya K Valiveti
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, Avera Health and Sciences Center, South Dakota State University, Brookings, SD 57007, USA
| | - Rakesh Dachineni
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, Avera Health and Sciences Center, South Dakota State University, Brookings, SD 57007, USA
| | - D Ramesh Kumar
- Department of Entomology, University of Kentucky, Lexington, KY 40546, USA
| | - Tana Lick
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, Avera Health and Sciences Center, South Dakota State University, Brookings, SD 57007, USA
| | - G Jayarama Bhat
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, College of Pharmacy and Allied Health Professions, Avera Health and Sciences Center, South Dakota State University, Brookings, SD 57007, USA
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The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention. Cancers (Basel) 2019; 11:cancers11030427. [PMID: 30917530 PMCID: PMC6468648 DOI: 10.3390/cancers11030427] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/16/2019] [Accepted: 03/22/2019] [Indexed: 12/22/2022] Open
Abstract
Flavonoids have emerged as promising compounds capable of preventing colorectal cancer (CRC) due to their anti-oxidant and anti-inflammatory properties. It is hypothesized that the metabolites of flavonoids are primarily responsible for the observed anti-cancer effects owing to the unstable nature of the parent compounds and their degradation by colonic microflora. In this study, we investigated the ability of one metabolite, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) to inhibit Cyclin Dependent Kinase (CDK) activity and cancer cell proliferation. Using in vitro kinase assays, we demonstrated that 2,4,6-THBA dose-dependently inhibited CDKs 1, 2 and 4 and in silico studies identified key amino acids involved in these interactions. Interestingly, no significant CDK inhibition was observed with the structurally related compounds 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) and phloroglucinol, suggesting that orientation of the functional groups and specific amino acid interactions may play a role in inhibition. We showed that cellular uptake of 2,4,6-THBA required the expression of functional SLC5A8, a monocarboxylic acid transporter. Consistent with this, in cells expressing functional SLC5A8, 2,4,6-THBA induced CDK inhibitory proteins p21Cip1 and p27Kip1 and inhibited cell proliferation. These findings, for the first time, suggest that the flavonoid metabolite 2,4,6-THBA may mediate its effects through a CDK- and SLC5A8-dependent pathway contributing to the prevention of CRC.
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20
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The Biological Significance and Regulatory Mechanism of c-Myc Binding Protein 1 (MBP-1). Int J Mol Sci 2018; 19:ijms19123868. [PMID: 30518090 PMCID: PMC6320933 DOI: 10.3390/ijms19123868] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 01/04/2023] Open
Abstract
Alternatively translated from the ENO gene and expressed in an array of vertebrate and plant tissues, c-Myc binding protein 1 (MBP-1) participates in the regulation of growth in organisms, their development and their environmental responses. As a transcriptional repressor of multiple proto-oncogenes, vertebrate MBP-1 interacts with other cellular factors to attenuate the proliferation and metastasis of lung, breast, esophageal, gastric, bone, prostrate, colorectal, and cervical cancer cells. Due to its tumor-suppressive property, MBP-1 and its downstream targets have been investigated as potential prognostic markers and therapeutic targets for various cancers. In plants, MBP-1 plays an integral role in regulating growth and development, fertility and abiotic stress responses. A better understanding of the functions and regulatory factors of MBP-1 in plants may advance current efforts to maximize plant resistance against drought, high salinity, low temperature, and oxidative stress, thus optimizing land use and crop yields. In this review article, we summarize the research advances in biological functions and mechanistic pathways underlying MBP-1, describe our current knowledge of the ENO product and propose future research directions on vertebrate health as well as plant growth, development and abiotic stress responses.
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21
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Bigelsen S. Evidence-based complementary treatment of pancreatic cancer: a review of adjunct therapies including paricalcitol, hydroxychloroquine, intravenous vitamin C, statins, metformin, curcumin, and aspirin. Cancer Manag Res 2018; 10:2003-2018. [PMID: 30034255 PMCID: PMC6049054 DOI: 10.2147/cmar.s161824] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Despite new and exciting research and renewed optimism about future therapy, current statistics of survival from pancreatic cancer remains dismal. Patients seeking alternative or complementary treatments should be warned to avoid the hype and instead look to real science. A variety of relatively safe and inexpensive treatment options that have shown success in preclinical models and/or retrospective studies are currently available. Patients require their physicians to provide therapeutic guidance and assistance in obtaining and administrating these various therapies. Paricalcitol, an analog of vitamin D, has been shown by researchers at the Salk Institute for Biological Studies to break though the protective stroma surrounding tumor cells. Hydroxychloroquine has been shown to inhibit autophagy, a process by which dying cells recycle injured organelles and internal toxins to generate needed energy for survival and reproduction. Intravenous vitamin C creates a toxic accumulation of hydrogen peroxide within cancer cells, hastening their death. Metformin inhibits mitochondrial oxidative metabolism utilized by cancer stem cells. Statins inhibit not only cholesterol but also other factors in the same pathway that affect cancer cell growth, protein synthesis, and cell cycle progression. A novel formulation of curcumin may prevent resistance to chemotherapy and inhibit pancreatic cancer cell proliferation. Aspirin therapy has been shown to prevent pancreatic cancer and may be useful to prevent recurrence. These therapies are all currently available and are reviewed in this paper with emphasis on the most recent laboratory research and clinical studies.
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Affiliation(s)
- Stephen Bigelsen
- Department of Allergy, Asthma and Immunology, Rutgers New Jersey Medical School, Newark, NJ, USA,
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22
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Cheng R, Liu YJ, Cui JW, Yang M, Liu XL, Li P, Wang Z, Zhu LZ, Lu SY, Zou L, Wu XQ, Li YX, Zhou Y, Fang ZY, Wei W. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells. Oncotarget 2018; 8:30252-30264. [PMID: 28415819 PMCID: PMC5444740 DOI: 10.18632/oncotarget.16325] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 03/09/2017] [Indexed: 02/07/2023] Open
Abstract
Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.
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Affiliation(s)
- Ran Cheng
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Ya-Jing Liu
- Institute of Biomedical Research, Shenzhen PKU-HKUST Medical Center, Shenzhen, 518036, China
| | - Jun-Wei Cui
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Man Yang
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Xiao-Ling Liu
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Peng Li
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Zhan Wang
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Li-Zhang Zhu
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Si-Yi Lu
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Li Zou
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Xiao-Qin Wu
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Yu-Xia Li
- Institute of Biomedical Research, Shenzhen PKU-HKUST Medical Center, Shenzhen, 518036, China
| | - You Zhou
- Institute of Biomedical Research, Shenzhen PKU-HKUST Medical Center, Shenzhen, 518036, China
| | - Zheng-Yu Fang
- Institute of Biomedical Research, Shenzhen PKU-HKUST Medical Center, Shenzhen, 518036, China
| | - Wei Wei
- Department of Breast Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China
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Chang HS, Park JS, Lee HS, Lyu J, Son JH, Choi IS, Shin HD, Park CS. Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma. BMC Pulm Med 2017; 17:210. [PMID: 29246216 PMCID: PMC5732499 DOI: 10.1186/s12890-017-0556-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 12/07/2017] [Indexed: 12/30/2022] Open
Abstract
Background We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype. Methods We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped. Results In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P = 0.001–0.004, OR = 0.59–0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P = 0.033), but the other four SNPs in hapblock2 were not. Conclusion To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition. Electronic supplementary material The online version of this article (10.1186/s12890-017-0556-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hun Soo Chang
- Department of Medical Bioscience, Graduate School, Soonchunhyang University, 22, Soonchunhyang-ro, Asan, Chungcheongnam-do, 336-745, Republic of Korea.
| | - Jong Sook Park
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174, Jung-Dong, Wonmi-Ku, Bucheon, Gyeonggi-Do, 420-021, Republic of Korea
| | - Ho Sung Lee
- Division of Respiratory Medicine, Soonchunhyang University Chunan Hospital, Chunan-Si, Chungcheongnam-do, 336-745, Republic of Korea
| | - Jiwon Lyu
- Division of Respiratory Medicine, Soonchunhyang University Chunan Hospital, Chunan-Si, Chungcheongnam-do, 336-745, Republic of Korea
| | - Ji-Hye Son
- Department of Medical Bioscience, Graduate School, Soonchunhyang University, 22, Soonchunhyang-ro, Asan, Chungcheongnam-do, 336-745, Republic of Korea
| | - Inseon S Choi
- Department of Allergy, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju, 61469, Republic of Korea
| | - Hyoung Doo Shin
- Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea.,Department of Genetic Epidemiology, SNP Genetics, Inc., 1407 14th Floor, Woolim-rall'ey B, Gasan-dong, Geumcheon-Gu, Seoul, 153-803, Republic of Korea
| | - Choon-Sik Park
- Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, 1174, Jung-Dong, Wonmi-Ku, Bucheon, Gyeonggi-Do, 420-021, Republic of Korea.
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24
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Targeting AMPK, mTOR and β-Catenin by Combined Metformin and Aspirin Therapy in HCC: An Appraisal in Egyptian HCC Patients. Mol Diagn Ther 2017; 22:115-127. [PMID: 29094287 DOI: 10.1007/s40291-017-0307-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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25
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Dachineni R, Kumar DR, Callegari E, Kesharwani SS, Sankaranarayanan R, Seefeldt T, Tummala H, Bhat GJ. Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin's chemopreventive effects against colorectal cancer. Int J Oncol 2017; 51:1661-1673. [PMID: 29075787 PMCID: PMC5673027 DOI: 10.3892/ijo.2017.4167] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 09/20/2017] [Indexed: 12/14/2022] Open
Abstract
Aspirin's potential as a drug continues to be evaluated for the prevention of colorectal cancer (CRC). Although multiple targets for aspirin and its metabolite, salicylic acid, have been identified, no unifying mechanism has been proposed to clearly explain its chemopreventive effects. Our goal here was to investigate the ability of salicylic acid metabolites, known to be generated through cytochrome P450 (CYP450) enzymes, and its derivatives as cyclin dependent kinase (CDK) inhibitors to gain new insights into aspirin's chemopreventive actions. Using in vitro kinase assays, for the first time, we demonstrate that salicylic acid metabolites, 2,3-dihydroxy-benzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), as well as derivatives 2,4-dihydroxybenzoic acid (2,4-DHBA), 2,6-dihydroxybenzoic acid (2,6-DHBA), inhibited CDK1 enzyme activity. 2,3-DHBA and 2,6-DHBA did not inhibit CDK2 and 4; however, both inhibited CDK-6 activity. Interestingly, another derivative, 2,4,6-trihydroxybenzoic acid (2,4,6-THBA) was highly effective in inhibiting CDK1, 2, 4 and 6 activity. Molecular docking studies showed that these compounds potentially interact with CDK1. Immunoblotting experiments showed that aspirin acetylated CDK1, and pre-incubation with salicylic acid and its derivatives prevented aspirin-mediated CDK1 acetylation, which supported the data obtained from molecular docking studies. We suggest that intracellularly generated salicylic acid metabolites through CYP450 enzymes within the colonic epithelial cells, or the salicylic acid metabolites generated by gut microflora may significantly contribute to the preferential chemopreventive effect of aspirin against CRC through inhibition of CDKs. This novel hypothesis and mechanism of action in aspirin's chemopreventive effects opens a new area for future research. In addition, structural modification to salicylic acid derivatives may prove useful in the development of novel CDK inhibitors in cancer prevention and treatment.
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Affiliation(s)
- Rakesh Dachineni
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - D Ramesh Kumar
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - Eduardo Callegari
- SD-BRIN Proteomic Facility, University of South Dakota School of Medicine, Vermillion, SD 57069, USA
| | - Siddharth S Kesharwani
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - Ranjini Sankaranarayanan
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - Teresa Seefeldt
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - Hemachand Tummala
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
| | - G Jayarama Bhat
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy and Allied Health Professions, Brookings, SD 57007, USA
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26
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Ryu JM, Jang GY, Woo KS, Kim TM, Jeong HS, Kim DJ. Effects of sorghum ethyl-acetate extract on PC3M prostate cancer cell tumorigenicity. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.07.063] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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27
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Beclin 1 acetylation impairs the anticancer effect of aspirin in colorectal cancer cells. Oncotarget 2017; 8:74781-74790. [PMID: 29088823 PMCID: PMC5650378 DOI: 10.18632/oncotarget.20367] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/25/2017] [Indexed: 12/21/2022] Open
Abstract
Regular use of aspirin can reduce cancer incidence, recurrence, metastasis and cancer-related mortality. Aspirin suppresses proliferation and induces apoptosis and autophagy in colorectal cancer cells, but the precise mechanism is not clear. In this study, we demonstrated that aspirin induced autophagosome formation in colorectal cancer cells, but autophagic degradation was blocked through aspirin-mediated Beclin 1 acetylation. Blocked autophagic degradation weakened aspirin-induced cell death. Collectively, our findings indicate the dual roles of aspirin on autophagy, and demonstrate a new mechanism by which Beclin 1 acetylation impairs the anticancer effect of aspirin in colorectal cancer cells.
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28
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Mitrugno A, Sylman JL, Ngo ATP, Pang J, Sears RC, Williams CD, McCarty OJT. Aspirin therapy reduces the ability of platelets to promote colon and pancreatic cancer cell proliferation: Implications for the oncoprotein c-MYC. Am J Physiol Cell Physiol 2016; 312:C176-C189. [PMID: 27903583 DOI: 10.1152/ajpcell.00196.2016] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/08/2016] [Accepted: 11/24/2016] [Indexed: 12/15/2022]
Abstract
Aspirin, an anti-inflammatory and antithrombotic drug, has become the focus of intense research as a potential anticancer agent owing to its ability to reduce tumor proliferation in vitro and to prevent tumorigenesis in patients. Studies have found an anticancer effect of aspirin when used in low, antiplatelet doses. However, the mechanisms through which low-dose aspirin works are poorly understood. In this study, we aimed to determine the effect of aspirin on the cross talk between platelets and cancer cells. For our study, we used two colon cancer cell lines isolated from the same donor but characterized by different metastatic potential, SW480 (nonmetastatic) and SW620 (metastatic) cancer cells, and a pancreatic cancer cell line, PANC-1 (nonmetastatic). We found that SW480 and PANC-1 cancer cell proliferation was potentiated by human platelets in a manner dependent on the upregulation and activation of the oncoprotein c-MYC. The ability of platelets to upregulate c-MYC and cancer cell proliferation was reversed by an antiplatelet concentration of aspirin. In conclusion, we show for the first time that inhibition of platelets by aspirin can affect their ability to induce cancer cell proliferation through the modulation of the c-MYC oncoprotein.
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Affiliation(s)
- Annachiara Mitrugno
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon; .,Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Joanna L Sylman
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon
| | - Anh T P Ngo
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon
| | - Jiaqing Pang
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon
| | - Rosalie C Sears
- Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.,Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon; and
| | - Craig D Williams
- Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.,College of Pharmacy, Oregon State University, Portland, Oregon
| | - Owen J T McCarty
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon.,Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, Oregon.,Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon
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29
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Tang Q, Liu Y, Li T, Yang X, Zheng G, Chen H, Jia L, Shao J. A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment. Oncotarget 2016; 7:73114-73129. [PMID: 27683033 PMCID: PMC5341967 DOI: 10.18632/oncotarget.12232] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 09/16/2016] [Indexed: 02/07/2023] Open
Abstract
Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.
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Affiliation(s)
- Qiao Tang
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Yajun Liu
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Tao Li
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Xiang Yang
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Guirong Zheng
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Hongning Chen
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Lee Jia
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
| | - Jingwei Shao
- Cancer Metastasis Alert and Prevention Center, Pharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, China
- Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention, Fuzhou University, Fuzhou, China
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30
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Sipos F, Firneisz G, Műzes G. Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases. World J Gastroenterol 2016; 22:7938-7950. [PMID: 27672289 PMCID: PMC5028808 DOI: 10.3748/wjg.v22.i35.7938] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.
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31
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Dachineni R, Ai G, Kumar DR, Sadhu SS, Tummala H, Bhat GJ. Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention. Mol Cancer Res 2016; 14:241-52. [PMID: 26685215 PMCID: PMC4794403 DOI: 10.1158/1541-7786.mcr-15-0360] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 12/03/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anticancer effects are still being elucidated. We hypothesized that aspirin's chemopreventive actions may involve cell-cycle regulation through modulation of the levels or activity of cyclin A2/cyclin-dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The downregulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. First, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Second, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, preincubation of CDK2 with salicylic acid dose-dependently quenched the fluorescence due to ANS. Third, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid downregulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention. IMPLICATIONS Biochemical and structural studies indicate that the antiproliferative actions of aspirin are mediated through cyclin A2/CDK2.
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Affiliation(s)
- Rakesh Dachineni
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota
| | - Guoqiang Ai
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota
| | - D Ramesh Kumar
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota
| | - Satya S Sadhu
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota
| | - Hemachand Tummala
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota
| | - G Jayarama Bhat
- Department of Pharmaceutical Sciences and Translational Cancer Research Center, South Dakota State University College of Pharmacy, Brookings, South Dakota.
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32
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Ai G, Dachineni R, Kumar DR, Marimuthu S, Alfonso LF, Bhat GJ. Aspirin acetylates wild type and mutant p53 in colon cancer cells: identification of aspirin acetylated sites on recombinant p53. Tumour Biol 2015; 37:6007-16. [PMID: 26596838 DOI: 10.1007/s13277-015-4438-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/12/2015] [Indexed: 12/19/2022] Open
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