Research on the Applications of AICAR in Clinical Medicine and Anti-Doping
DOI:
https://doi.org/10.54097/3xxk2f76Keywords:
AICAR, AMPK activators, metabolic regulators, doping testingAbstract
Objectives: The objective of this review is to examine the role of AICAR as an AMP-activated protein kinase (AMPK) activator and its potential applications in clinical conditions, as well as its significance in anti-doping research. Methods: This review analyzes the current literature on AICAR, focusing on its mechanisms of action as a cell-permeable AMPK activator and its impact on cellular energy homeostasis. Furthermore, it explores the extensive research regarding AICAR's potential applications in cardiovascular diseases, diabetes, organ transplantation, neurodegenerative diseases, and cancer, as well as its implications for athletic performance and muscle glucose uptake. Results: AICAR has emerged as a crucial regulator of cellular energy homeostasis through its activation of AMPK, with implications for various clinical conditions. Additionally, its potential to enhance athletic performance and stimulate muscle glucose uptake has garnered considerable attention in the realm of anti-doping research. Conclusions: This review highlights the multifaceted potential of AICAR in clinical applications and anti-doping research, emphasizing its role as an AMPK activator and its impact on cellular energy homeostasis. The findings underscore the significance of ongoing research and development of AICAR in medicine and anti-doping efforts.
Downloads
References
[1] Iglesias M I, Ye J M, Frangioudakis G, et al. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats [J]. Diabetes, 2002, 51: 2886–2894.
[2] Liu F, Zhou W, Liu X, et al. AICAR induces cell death in LKB1-deficient NSCLC [J]. Cancer Res, 2013, 73 (8): 1975.
[3] Montraveta A, Xargay-Torrent S, Lopez-Guerra M, et al. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in vivo and in vitro models of mantle cell lymphoma [J]. Oncotarget, 2014, 5: 726–739.
[4] NCCN_Guidelines (2014) NCCN clinical guidelines in Oncology-Breast Cancer.
[5] Wallace D C. Mitochondria and cancer [J]. Nature Reviews Cancer, 2012, 12: 685–698.
[6] Hardie D G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy [J]. Nature Reviews Molecular Cell Biology, 2007, 8: 774–785.
[7] Feng W, Gentles A, Nair RV, Huang M, Lin Y, et al. Targeting unique metabolic properties of breast tumor initiating cells. Stem Cells, 2014, 32: 1734–1745.
[8] Faubert B, Boily G, Izreig S, et al. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo [J]. Cell Metabolic, 2013, 17: 113–124.
[9] Tamás F, et al. "Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK) and FOXO1." [J]. PLOS ONE, 2017, 11: 2.
[10] Siegel R L, Miller K D, Jemal A. Cancer statistics [J]. CA Cancer Journal of Clinical, 2018, 68: 7–30.
[11] Litwin M S, Tan, H J. The diagnosis and treatment of prostate cancer: A review [J]. JAMA, 2017, 317: 2532–2542.
[12] Yuan Ma. AR-V7 plays a role in resistance to endocrine therapy in prostate cancer and its molecular mechanisms. Medical University.
[13] Lameire N, Van Biesen W, Vanholder R. Acute renal failure [J]. Lancet, 2005, 365: 417–430.
[14] Kunzendorf U, Haase M, Rolver L, Haase-Fielitz A. Novel aspects of pharmacological therapies for acute renal failure [J]. Drugs, 2010, 70: 1099–1114.
[15] Yongjiu Wang. Resveratrol's neuroprotective effect on recurrent ischemic stroke rats [D]. Tianjin Medical University. 2012.
[16] Deyuan Meng, Yuanyuan Chen, Rong Qin, et al. The role and molecular mechanism of the JAK/STAT pathway-related gene FDGM1 in gliomas [C]//National Conference and Academic Symposium of the China Genetic Society. 2013.
[17] yuan Cheng, Youmin Wang, Xiaojie Ding. Obesity rats skeletal muscle AMPK expression and its relationship with glucose and lipid metabolism [J]. Journal of Anhui Medical University. 2010, 45 (2): 180-183.
[18] Null R, Consultation W. Obesity: Preventing and managing the global Epidemic [J]. Geneva World Health Organization, 2000, 15 (1): 18-30.
[19] Ying Li. Study on the regulatory effect of AMPK and the solidification of stasis-eliminating-facilitated-flow prescription on the renal protection in diabetic nephropathy[D]. Chengdu University of Traditional Chinese Medicine. 2017.
[20] Lin Luo. Aerobic training activates AMPK and affects Nrf2-mediated antioxidant effects in skeletal muscle of mice [D]. Beijing Sport University. 2018.
[21] Feng Y Z, Nikolic N, Bakke S S, et al. PPARδ activation in human myotubes increases mitochondrial fatty acid oxidative capacity and reduces glucose utilization by a switch in substrate preference [J]. Archives of Physiology and Biochemistry, 2014, 120 (1): 12–21.
[22] Jose C, Hebert-Chatelain E, Bellance N, et al. AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation [J]. Biochim Biophys Acta, 2011, 1807: 707–718.
[23] Lanner J T, Georgiou D K, Dagnino-Acosta A, et al. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation [J]. Nature Medicine, 2012, 18: 244–251.
[24] Bronnum-Hansen H, Juel K, Davidsen M, et al. Impact of selected risk factors on expected lifetime without long-standing, limiting illness in Denmark [J]. Preventive Medicine, 2007, 45 (1): 49–53.
[25] Cresser J, Bonen A, Chabowski A, et al. Oral administration of a PPAR-delta agonist to rodents worsens, not improves, maximal insulin-stimulated glucose transport in skeletal muscle of different fibers [J]. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2010, 299: R470-9.
[26] Wong J K Y, Wan T S M. Doping control analyses in horse racing: A clinician’s guide [J]. The Veterinary Journal, 2014, 200 (1): 8-16.
[27] Article 6E-Out-of-Competition Testing, International Agreement on Breeding, Racing and Wagering (IABRW), International Federation of Horseracing Authorities (IFHA). Available at: http://www.ifhaonline.org/default.asp? section=IABRW&area =2#a6e (accessed 29 March 2017.
[28] M. De Neef. The new EPO-GW1516, AICAR and their use in cycling. 2013 Availableat:http:// cyclingtips.com.au/2013/04/the-new-epo-gw1516-AICAR-and-their-use-incycling/ (accessed 29 March 2017.
[29] Thomas A, Beuck S, Eickhoff J C, et al. Quantification of urinary AICAR concentrations as a matter of doping controls [J]. Analytical Bioanalytical Chemistry, 2010, 396: 2899–2908.
[30] Guddat S, Solymos E, Orlovius A, Thomas A, et al. High-throughput screening for various classes of doping agents using a new ‘dilute-and-shoot’ liquid chromatography-tandem mass spectrometry multi-target approach [J]. Drug Testing and Analysis, 2011, 9: 836-850.
[31] Thomas A, Vogel M, Piper T, et al. Quantification of AICAR-ribotide concentrations in red blood cells by means of LC-MS/MS [J]. Analytical and Bioanalytical Chemistry, 2013, 405 (30): 9703-9712.
[32] Görgens C, Guddat S, Anne-Katrin O, et al. "Dilute-and-inject" multi-target screening assay for highly polar doping agents using hydrophilic interaction liquid chromatography high resolution/high accuracy mass spectrometry for sports drug testing [J]. Analytical and bioanalytical chemistry, 2015, 407 (18): 5365-5379.
[33] Kwok W H, Choi T L S, Kwok K Y, et al. Doping control analysis of 46 polar drugs in horse plasma and urine using a 'dilute-and-shoot' ultra high performance liquid chromatography-high resolution mass spectrometry approach [J]. Journal of chromatography A, 2016, 1451: 41-49.
[34] Yu Hong, Youxuan Xu. Establishment and Application of LC-MS/MS Detection Method for AICAR [J].Journal of Chinese Sports Medicine, 2016, 35 (03): 274–278.
[35] Cawley A T, Flenker U. The application of carbon isotope ratio mass spectrometry to doping control [J]. Journal of mass spectrometry, 2008, 43 (7): 854–864.
[36] Buisson C, Frelat C, Mongongu C, et al. Implementation of AICAR analysis by GC-C-IRMS for anti-doping purposes [J]. Drug Testing and Analysis, 2017, 9: 1704–1712.
[37] Sobolevsky T, Ahrens B. Urinary concentrations of AICAR and mannitol in athlete population [J]. Drug Testing and Analysis, 2019, 11(3).
[38] Višnjić D, Lalić H, Dembitz V, et al. AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review[J]. Cells, 2021, 10(5): 1095.
[39] Gao J, Xiong R, Xiong D, et al. The Adenosine Monophosphate (AMP) Analog, 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Inhibits Hepatosteatosis and Liver Tumorigenesis in a High-Fat Diet Murine Model Treated with Diethylnitrosamine (DEN)[J]. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 2018, 24: 8533-8543.
[40] Krishnan U A, Viswanathan P, Venkataraman A C. AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice[J]. Tissue & Cell, 2023, 82: 102054.
[41] Zineldeen D H, Tahoon N M, Sarhan N I. AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats[J]. International Journal of Molecular Sciences, 2023, 24(4): 3367.
[42] Ahmad I, Molyvdas A, Jian M Y, et al. AICAR decreases acute lung injury by phosphorylating AMPK and upregulating heme oxygenase-1[J]. European Respiratory Journal, 2021, 58(6): 2003694.
[43] Hashempour S, Shahabadi N, Adewoye A, et al. Binding Studies of AICAR and Human Serum Albumin by Spectroscopic, Theoretical, and Computational Methodologies[J]. Molecules, 2020, 25(22): 5410.
[44] Kong L, Zhang H, Lu C, et al. AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation[J]. Frontiers in Pharmacology, 2021, 12: 724514.
[45] Samsonov M V, Podkuychenko N V, Khapchaev A Y, et al. AICAR Protects Vascular Endothelial Cells from Oxidative Injury Induced by the Long-Term Palmitate Excess[J]. International Journal of Molecular Sciences, 2021, 23(1): 211.
[46] Misquitta N S, Ravel-Chapuis A, Jasmin B J. Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner[J]. Human Molecular Genetics, 2023, 32(4): 551-566.
[47] Yan S, Yuan D, Li Q, et al. AICAR enhances the cytotoxicity of PFKFB3 inhibitor in an AMPK signaling-independent manner in colorectal cancer cells[J]. Medical Oncology, 2022, 39(1): 1-12.
[48] Alba G, Martínez R, Postigo-Corrales F, et al. AICAR Stimulates the Pluripotency Transcriptional Complex in Embryonic Stem Cells Mediated by PI3K, GSK3β, and β-Catenin[J]. ACS Omega, 2020, 5(32): 20270-20282.
[49] Gonzalez-Franquesa A, Peijs L, Cervone D T, et al. Insulin and 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Differentially Regulate the Skeletal Muscle Cell Secretome[J]. Proteomes, 2021, 9(3): 37.
[50] Rasch D, Dray S, Santos J D, et al. The Effect of AICAR-Induced AMPK Activation on Gene Expression in Sarcopenic Muscle[J]. International Journal of Exercise Science: Conference Proceedings, 2023, 14(3).
[51] Tripathi V, Jaiswal P, Assaiya A, et al. Anti-cancer Effects of 5-Aminoimidazole-4-Carboxamide-1-β-D-Ribofuranoside (AICAR) on Triple-negative Breast Cancer (TNBC) Cells: Mitochondrial Modulation as an Underlying Mechanism[J]. Current Cancer Drug Targets, 2022, 22(3): 245-256.
[52] Pyla R, Hartney T J, Segar L. AICAR promotes endothelium-independent vasorelaxation by activating AMP-activated protein kinase via increased ZMP and decreased ATP/ADP ratio in aortic smooth muscle[J]. Journal of Basic and Clinical Physiology and Pharmacology, 2022, 33(6): 759-768.
[53] Bustraan, Sophia; Bennett, Jane; Whilding, Chad; Pennycook, Betheney R.; Smith, David; Barr, Alexis R.; Read, Jon; Carling, David; Pollard, Alice AMP-activated protein kinase activation suppresses leptin expression independently of adipogenesis in primary murine adipocytes [J], BIOCHEMICAL JOURNAL, 2024, 481, 5, 345-362. 10.1042/BCJ20240003
[54] Wang, Haiyan; Zheng, Amy; Thorley, Dominic; Arias, Edward B.; Cartee, Gregory D. Independent and combined effects of calorie restriction and AICAR on glucose uptake and insulin signaling in skeletal muscles from 24-month-old female and male rats [J], APPLIED PHYSIOLOGY NUTRITION AND METABOLISM, 2024 10.1139/apnm-2023-0522
[55] Zhu, Huimin; Zhao, Tangna; Zeng, Wanbo; Dong, Xiao; Luo, Yuan; Li, Xiang; Zhang, Aiping; Shi, Weiguo; Xu, Liang. Adenosine and its derivatives improve exercise performance and exert anti-fatigue effects via AMPK/PGC-1α signaling pathway in mice [J], ARABIAN JOURNAL OF CHEMISTRY, 2024, 17, 1, 10.1016/j.arabjc.2023.105490
[56] Aikawa, Akiyoshi; Kozako, Tomohiro; Kato, Naho; Ohsugi, Takeo; Honda, Shin-ichiro. Anti-tumor activity of 5-aminoimidazole-4-carboxamide riboside with AMPK-independent cell death in human adult T-cell leukemia/lymphoma [J], EUROPEAN JOURNAL OF PHARMACOLOGY, 2023, 961, 10.1016/j.ejphar.2023.176180.
[57] Owaki, Reina; Aoki, Hiromasa; Toriuchi, Kohki; Inoue, Yasumichi; Hayashi, Hidetoshi; Takeshita, Satoru; Kakita, Hiroki; Yamada, Yasumasa; Aoyama, Mineyoshi. AMPK activators suppress cholesterol accumulation in macrophages via suppression of the mTOR pathway [J], EXPERIMENTAL CELL RESEARCH, 2023, 432, 1. 10.1016/j.yexcr.2023.113784
[58] Michel, J. Max; Godwin, Joshua S.; Plotkin, Daniel L.; Mesquita, Paulo H. C.; McIntosh, Mason C.; Ruple, Bradley A.; Libardi, Cleiton A.; Mobley, C. Brooks; Kavazis, Andreas N.; Roberts, Michael D. Proteolytic markers associated with a gain and loss of leg muscle mass with resistance training followed by high-intensity interval training [J], EXPERIMENTAL PHYSIOLOGY, 2023, 108, 10, 1268, 1281. 10.1113/EP091286
[59] Gu, Shi-Hong; Lin, Pei-Ling. Signaling in cAMP-stimulated ecdysteroidogenesis in prothoracic glands of the silkworm, Bombyx mori [J], JOURNAL OF INSECT PHYSIOLOGY, 2023, 149. 10.1016/j. jinsphys.2023.104548
[60] Raun, Steffen H.; Ali, Mona S.; Han, Xiuqing; Henriquez-Olguin, Carlos; Pham, T. C. Phung; Meneses-Valdes, Roberto; Knudsen, Jonas R.; Willemsen, Anna C. H.; Larsen, Steen; Jensen, Thomas E.; Langen, Ramon; Sylow, Lykke. Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice [J], JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, 2023, 14, 4, 1631-1647. 10.1002/jcsm.13238
[61] Yang, Heyu; Wang, Yujia; Zhen, Shuqing; Wang, Banghua; Jiao, Ming; Liu, Ling; Li, Dai; Zhu, Haili; Xie, Min. AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation [J], ACTA BIOCHIMICA ET BIOPHYSICA SINICA, 2023, 55, 3, 460-471. 10.3724/abbs.2023039.
[62] Aftab, Fareesa; Rodriguez-Fuguet, Alice; Silva, Luis; Kobayashi, Ikei S.; Sun, Jiao; Politi, Katerina; Levantini, Elena; Zhang, Wei; Kobayashi, Susumu S.; Zhang, Wen Cai. An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1[J], BRITISH JOURNAL OF CANCER, 2023, 128, 9, 1647-1664. 10.1038/s41416-023-02196-z
[63] Wu, Jianbo; Gulati, Shelly; Teague, April M. M.; Kim, Youngsil; Tryggestad, Jeanie B. B.; Jiang, Shaoning. AMPK Regulates DNA Methylation of PGC-1α and Myogenic Differentiation in Human Mesenchymal Stem Cells [J], STEM CELLS AND DEVELOPMENT, 2023, 32, 131-139. 10.1089/scd.2022.0226.
[64] Khamaru, Poulomi; Chakraborty, Sayan; Bhattacharyya, Arindam. AMPK activator AICAR in combination with anti-mouse IL10 mAb restores the functionality of intra-tumoral Tfh cells in the 4T1 mouse model [J], CELLULAR IMMUNOLOGY, 2022, 382. 10.1016/j.cellimm.2022.104639
[65] Misquitta, Naomi S.; Ravel-Chapuis, Aymeric; Jasmin, Bernard J. Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner [J], HUMAN MOLECULAR GENETICS, 2023, 32, 4, 551-566. 10.1093/hmg/ddac222
[66] Joy, Praisy; Madhuri, Vrisha; Palocaren, Thomas; Das, Sweta; Abraham, Suneetha Susan Cleave; Korula, Sophy; Koshy, Beena; Jose, John; Chandran, Mahalakshmi; Danda, Sumita. Case report of a rare purine synthesis disorder due to 5-aminoimidazole-4-carboxamide ribonucleotide form yltransferase (AICAR) deficiency [J], BRAIN & DEVELOPMENT, 2022, 44, 9, 645-649. 10.1016/j.braindev.2022.05.004
[67] Kim, Hye Jin; Kim, Youn Ju; Seong, Je Kyung. AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model [J], JOURNAL OF PHYSIOLOGY-LONDON, 2022, 600, 10, 2359-2376. 10.1113/JP282999
[68] Calixto, Jouber; Johnson, Connor; Smith, Andrew; Brodowski, Kole; Wilcox, Shalene H.; Hill, Jonathon T.; Thomson, David M. Chronic AICAR treatment enhances anabolic signaling in sarcopenic skeletal muscle [J]. FASEB JOURNAL, 2022, 36. 10.1096/fasebj.2022.36.S1.R5697
[69] Pace, Tyson; Marchant, Erik; Wilkinson, Cameron; Ashby, Jared S.; Galvan, David A.; Rojas, Joseph; McClune, Derek; Saunders, Oliver; Hancock, Chad R.; Thomson, David M. In Vivo Effects of AICAR and Prodrug 39 (P39) on Anabolic Pathways Following Refeeding in Skeletal Muscle [J]. FASEB JOURNAL, 2022, 36. 10.1096/fasebj.2022.36.S1.L7910
[70] Ahmad, Israr; Molyvdas, Adam; Jian, Ming-Yuan; Zhou, Ting; Traylor, Amie M.; Cui, Huachun; Liu, Gang; Song, Weifeng; Agarwal, Anupam; Jilling, Tamas; Aggarwal, Saurabh; Matalon, Sadis. AICAR decreases acute lung injury by phosphorylating AMPK and upregulating heme oxygenase-1 [J]. EUROPEAN RESPIRATORY JOURNAL, 2021, 58, 6. 10.1183/13993003.03694-2020
[71] Bottcher, Katrin; Longato, Lisa; Marrone, Giusi; Mazza, Giuseppe; Ghemtio, Leo; Hall, Andrew; Luong, Tu Vinh; Caruso, Stefano; Viollet, Benoit; Zucman-Rossi, Jessica; Pinzani, Massimo; Rombouts, Krista. AICAR and compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2021, 320, 4, G543-G556. 10.1152/ajpgi.00262.2020
[72] Liu, Jin; Liang, Long; Li, Xin; Peng, Yuan liang; Zhang, Ji; Wang, Xiao long; Liu, Jing; Nie, Ling. AICAR suppresses cell proliferation and synergizes with decitabine in myelodysplastic syndrome via DNA damage induction [J]. BIOTECHNOLOGY LETTERS, 2021, 43, 6, 1131-1142. 10.1007/s10529-021-03112-2
[73] Zhu, Xiao-ying; Liu, Wen; Liang, Hai-tao; Tang, Ling; Zou, Ping; You, Yong; Zhu, Xiao-jian. AICAR and Decitabine Enhance the Sensitivity of K562 Cells to Imatinib by Promoting Mitochondrial Activity [J]. CURRENT MEDICAL SCIENCE, 2020, 40, 871-878. 10.1007/s11596-020-2266-1
[74] Lane, Sydney L.; Houck, Julie A.; Doyle, Alexandrea S.; Bales, Elise S.; Lorca, Ramon A.; Julian, Colleen G.; Moore, Lorna G. AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow [J]. JOURNAL OF PHYSIOLOGY-LONDON, 2020, 598, 4093-4105. 10.1113/JP279341
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Highlights in Science, Engineering and Technology
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
