The Neuro- Cardio- and Hepato- Protective Effects of Namodenoson are Mediated by Adiponectin
Main Article Content
Abstract
Namodenoson (CF102, Cl-IB-MECA) is a small, water-insoluble, orally bioavailable highly selective A3 adenosine receptor agonist. Namodenoson exerts its clinical activity by binding to the A3 adenosine receptor, which has a role in both inflammation and cancer and was shown to be highly expressed on cancer and inflammatory cells. Namodenoson is currently under clinical development as a treatment for hepatocellular carcinoma (phase 3 trial is ongoing) and metabolic dysfunction-associated steatohepatitis (phase 2b trial is ongoing). Beyond the liver, namodenoson has also been shown to provide protective effects in the central nervous system and the cardiovascular system. The protective effects of namodenoson include anti-ischemic, anti-inflammatory, anti-toxicity, and anti-fibrotic effects. Adiponectin is a hormone produced by adipocytes. It is a polypeptide containing 244 amino acids and can be found in 3 forms (low, moderate, and high molecular weight). It binds to 3 receptors: adiponectin receptor 1, adiponectin receptor 2, and T-cadherin. Adiponectin plays protective roles in a variety of physiological functions across many organs, including the central nervous system, cardiovascular system, and the liver, as well as the kidneys, muscles, and bones. Similar to namodenoson, adiponectin provides anti-ischemic, anti-inflammatory, as well as anti-fibrotic protection, but it is also involved in energy regulation, protection against oxidative stress, promotion of insulin sensitivity, and more. The current review discusses the protective effects of namodenoson in the central nervous system, cardiovascular system, and liver focusing on the available preclinical evidence supporting such protective effects in each system, and presents evidence from preclinical models and translational data from the phase 2 trial in metabolic dysfunction-associated steatohepatitis supporting the hypothesis that namodenoson’s protective effects are mediated via pathways that involve adiponectin.
Keywords:
A3AR, adiponectin, cardioprotection, hepatoprotection, namodenoson, neuroprotection
Article Details
How to Cite
ETZION, Ohad et al.
The Neuro- Cardio- and Hepato- Protective Effects of Namodenoson are Mediated by Adiponectin.
Medical Research Archives, [S.l.], v. 13, n. 2, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6343>. Date accessed: 17 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6343.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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31. Chanyshev B, Shainberg A, Isak A, et al. Anti-ischemic effects of multivalent dendrimeric A(3) adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart. Pharmacol Res. 2012; 65(3):338-46.
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35. Emanuelov AK, Shainberg A, Chepurko Y, et al. Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage. Biochem Pharmacol. 2010; 79(2):180-7.
36. Galal A, El-Bakly WM, Al Haleem EN, et al. Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol. 2016; 77(2):309-22.
37. Ohana G, Cohen S, Rath-Wolfson L, et al. A3 adenosine receptor agonist, CF102, protects against hepatic ischemia/reperfusion injury following partial hepatectomy. Mol Med Rep. 2016; 14(5):4335-41.
38. Cohen S, Stemmer SM, Zozulya G, et al. CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol. 2011; 226(9):2438-47.
39. Fishman P, Cohen S, Itzhak I, et al. The A3 adenosine receptor agonist, namodenoson, ameliorates nonalcoholic steatohepatitis in mice. Int J Mol Med. 2019; 44(6):2256-64.
40. Yang L, Gao ZW, Wang X, et al. The different effects of four adenosine receptors in liver fibrosis. Front Pharmacol. 2024; 15:1424624.
41. Nishimura M, Izumiya Y, Higuchi A, et al. Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms. Circulation. 2008; 117(2):216-23.
42. Miao J, Shen LH, Tang YH, et al. Overexpression of adiponectin improves neurobehavioral outcomes after focal cerebral ischemia in aged mice. CNS Neurosci Ther. 2013; 19(12):969-77.
43. Ouchi N, Shibata R, Walsh K. Cardioprotection by adiponectin. Trends Cardiovasc Med. 2006; 16(5):141-6.
44. Yue H, Zhang Q, Chang S, et al. Adiponectin protects against myocardial ischemia-reperfusion injury: a systematic review and meta-analysis of preclinical animal studies. Lipids Health Dis. 2024; 23(1):51.
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46. Polyzos SA, Kountouras J, Zavos C, et al. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab. 2010; 12(5):365-83.
47. Kamada Y, Matsumoto H, Tamura S, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007; 47(4):556-64.
48. Huang Z, Sung HK, Yan X, et al. The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis. Clin Transl Sci. 2024; 17(6):e13760.
49. Yu J, Ahn S, Kim HJ, et al. Polypharmacology of N(6)-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and related A(3) adenosine receptor ligands: Peroxisome proliferator activated receptor (PPAR) gamma partial agonist and PPARdelta antagonist activity suggests their antidiabetic potential. J Med Chem. 2017; 60(17):7459-75.
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52. Stemmer SM, Benjaminov O, Medalia G, et al. CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study. Oncologist. 2013; 18(1):25-6.
53. Stemmer SM, Manojlovic NS, Marinca MV, et al. Namodenoson in advanced hepatocellular carcinoma and Child-Pugh B cirrhosis: Randomized placebo-controlled clinical trial. Cancers (Basel). 2021; 13(2).
2. Fishman P. Drugs targeting the A3 adenosine receptor: Human clinical study data. Molecules. 2022; 27(12).
3. Etzion O, Bareket-Samish A, Yardeni D, et al. Namodenoson at the crossroad of metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. Biomedicines. 2024; 12(4).
4. Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov. 2006; 5(3):247-64.
5. Doyle TM, Janes K, Xiao WH, et al. Mitochondrial A(3) adenosine receptor as a mechanism for the protective effects of A(3)AR agonists on chemotherapy-induced neuropathic pain. J Neurosci. 2024. Online ahead of print.
6. Clinicaltrials.gov. Description of the "Namodenoson in the treatment of advanced hepatocellular carcinoma in patients with Child-Pugh Class B7 cirrhosis (LIVERATION)" study (NCT05201404). Available at: https://www.clinicaltrials.gov/study/NCT05201404. Accessed Jan 2, 2025.
7. Clinicaltrials.gov. Description of the "Namodenoson in the treatment of non-alcoholic steatohepatitis (NASH)" study (NCT04697810). Available at: https://clinicaltrials.gov/search?term=NCT04697810. Accessed Jan 2, 2025.
8. Khoramipour K, Chamari K, Hekmatikar AA, et al. Adiponectin: Structure, physiological functions, role in diseases, and effects of nutrition. Nutrients. 2021; 13(4).
9. Bloemer J, Pinky PD, Govindarajulu M, et al. Role of adiponectin in central nervous system disorders. Neural Plast. 2018; 2018:4593530.
10. Kusminski CM, McTernan PG, Schraw T, et al. Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia. 2007; 50(3):634-42.
11. Chen Z, Janes K, Chen C, et al. Controlling murine and rat chronic pain through A3 adenosine receptor activation. FASEB J. 2012; 26(5):1855-65.
12. Haddad M, Alsalem M, Aldossary SA, et al. The role of adenosine receptor ligands on inflammatory pain: possible modulation of TRPV1 receptor function. Inflammopharmacology. 2023; 31(1):337-47.
13. Chen GJ, Harvey BK, Shen H, et al. Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J Neurosci Res. 2006; 84(8):1848-55.
14. Pugliese AM, Coppi E, Volpini R, et al. Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen-glucose deprivation episodes of different duration. Biochem Pharmacol. 2007; 74(5):768-79.
15. Luo C, Yi B, Tao G, et al. Adenosine A3 receptor agonist reduces early brain injury in subarachnoid haemorrhage. Neuroreport. 2010; 21(13):892-6.
16. Li P, Li X, Deng P, et al. Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats. Aging (Albany NY). 2020; 13(1):694-713.
17. Lillo A, Serrano-Marin J, Lillo J, et al. Gene regulation in activated microglia by adenosine A(3) receptor agonists: a transcriptomics study. Purinergic Signal. 2024; 20(3):237-45.
18. Serrano-Marin J, Valenzuela R, Delgado C, et al. Neuroprotective compounds alter the expression of genes coding for proteins related to mitochondrial function in activated microglia. Mitochondrion. 2024; 78:101934.
19. Mattar M, Umutoni F, Hassan MA, et al. Chemotherapy-induced peripheral neuropathy: A recent update on pathophysiology and treatment. Life (Basel). 2024; 14(8).
20. Stambaugh K, Jacobson KA, Jiang JL, et al. A novel cardioprotective function of adenosine A1 and A3 receptors during prolonged simulated ischemia. Am J Physiol. 1997; 273(1 Pt 2):H501-5.
21. Thourani VH, Ronson RS, Jordan JE, et al. Adenosine A3 pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction. Ann Thorac Surg. 1999; 67(6):1732-7.
22. Shneyvays V, Mamedova LK, Leshem D, et al. Insights into the cardioprotective function of adenosine A(1) and A(3) receptors. Exp Clin Cardiol. 2002; 7(2-3):138-45.
23. Harrison GJ, Cerniway RJ, Peart J, et al. Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res. 2002; 53(1):147-55.
24. Maddock HL, Mocanu MM, Yellon DM. Adenosine A(3) receptor activation protects the myocardium from reperfusion/reoxygenation injury. Am J Physiol Heart Circ Physiol. 2002; 283(4):H1307-13.
25. Hochhauser E, Kaminski O, Shalom H, et al. Role of adenosine receptor activation in antioxidant enzyme regulation during ischemia-reperfusion in the isolated rat heart. Antioxid Redox Signal. 2004; 6(2):335-44.
26. Zatta AJ, Matherne GP, Headrick JP. Adenosine receptor-mediated coronary vascular protection in post-ischemic mouse heart. Life Sci. 2006; 78(21):2426-37.
27. Ge ZD, Peart JN, Kreckler LM, et al. Cl-IB-MECA [2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. J Pharmacol Exp Ther. 2006; 319(3):1200-10.
28. Hochhauser E, Leshem D, Kaminski O, et al. The protective effect of prior ischemia reperfusion adenosine A1 or A3 receptor activation in the normal and hypertrophied heart. Interact Cardiovasc Thorac Surg. 2007; 6(3):363-8.
29. Ge ZD, van der Hoeven D, Maas JE, et al. A(3) adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells. J Mol Cell Cardiol. 2010; 49(2):280-6.
30. Hussain A, Gharanei AM, Nagra AS, et al. Caspase inhibition via A3 adenosine receptors: a new cardioprotective mechanism against myocardial infarction. Cardiovasc Drugs Ther. 2014; 28(1):19-32.
31. Chanyshev B, Shainberg A, Isak A, et al. Anti-ischemic effects of multivalent dendrimeric A(3) adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart. Pharmacol Res. 2012; 65(3):338-46.
32. Duangrat R, Parichatikanond W, Chanmahasathien W, et al. Adenosine A(3) receptor: From molecular signaling to therapeutic strategies for heart diseases. Int J Mol Sci. 2024; 25(11).
33. Linders AN, Dias IB, Lopez Fernandez T, et al. A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging. NPJ Aging. 2024; 10(1):9.
34. Shneyvays V, Mamedova L, Zinman T, et al. Activation of A(3)adenosine receptor protects against doxorubicin-induced cardiotoxicity. J Mol Cell Cardiol. 2001; 33(6):1249-61.
35. Emanuelov AK, Shainberg A, Chepurko Y, et al. Adenosine A3 receptor-mediated cardioprotection against doxorubicin-induced mitochondrial damage. Biochem Pharmacol. 2010; 79(2):180-7.
36. Galal A, El-Bakly WM, Al Haleem EN, et al. Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol. 2016; 77(2):309-22.
37. Ohana G, Cohen S, Rath-Wolfson L, et al. A3 adenosine receptor agonist, CF102, protects against hepatic ischemia/reperfusion injury following partial hepatectomy. Mol Med Rep. 2016; 14(5):4335-41.
38. Cohen S, Stemmer SM, Zozulya G, et al. CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol. 2011; 226(9):2438-47.
39. Fishman P, Cohen S, Itzhak I, et al. The A3 adenosine receptor agonist, namodenoson, ameliorates nonalcoholic steatohepatitis in mice. Int J Mol Med. 2019; 44(6):2256-64.
40. Yang L, Gao ZW, Wang X, et al. The different effects of four adenosine receptors in liver fibrosis. Front Pharmacol. 2024; 15:1424624.
41. Nishimura M, Izumiya Y, Higuchi A, et al. Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms. Circulation. 2008; 117(2):216-23.
42. Miao J, Shen LH, Tang YH, et al. Overexpression of adiponectin improves neurobehavioral outcomes after focal cerebral ischemia in aged mice. CNS Neurosci Ther. 2013; 19(12):969-77.
43. Ouchi N, Shibata R, Walsh K. Cardioprotection by adiponectin. Trends Cardiovasc Med. 2006; 16(5):141-6.
44. Yue H, Zhang Q, Chang S, et al. Adiponectin protects against myocardial ischemia-reperfusion injury: a systematic review and meta-analysis of preclinical animal studies. Lipids Health Dis. 2024; 23(1):51.
45. Vachliotis ID, Valsamidis I, Polyzos SA. Tumor necrosis factor-alpha and adiponectin in nonalcoholic fatty liver disease-associated hepatocellular carcinoma. Cancers (Basel). 2023; 15(21).
46. Polyzos SA, Kountouras J, Zavos C, et al. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab. 2010; 12(5):365-83.
47. Kamada Y, Matsumoto H, Tamura S, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007; 47(4):556-64.
48. Huang Z, Sung HK, Yan X, et al. The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis. Clin Transl Sci. 2024; 17(6):e13760.
49. Yu J, Ahn S, Kim HJ, et al. Polypharmacology of N(6)-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and related A(3) adenosine receptor ligands: Peroxisome proliferator activated receptor (PPAR) gamma partial agonist and PPARdelta antagonist activity suggests their antidiabetic potential. J Med Chem. 2017; 60(17):7459-75.
50. Can-Fite Ltd., data on file. 2025.
51. Safadi R, Braun M, Francis A, et al. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment Pharmacol Ther. 2021; 54(11-12):1405-15.
52. Stemmer SM, Benjaminov O, Medalia G, et al. CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study. Oncologist. 2013; 18(1):25-6.
53. Stemmer SM, Manojlovic NS, Marinca MV, et al. Namodenoson in advanced hepatocellular carcinoma and Child-Pugh B cirrhosis: Randomized placebo-controlled clinical trial. Cancers (Basel). 2021; 13(2).