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  Acadesine

Description of acadesine: acadesine is a 5-aminoimidazole-4-carboxamide (AICA) riboside, a purine nucleoside analog, and a nucleotide biosynthesis precursor with B cell pro-apoptotic activity. Following cellular uptake, acadesine is phosphorylated to AICA ribotide (ZMP), which mimics 5'-adenosine monophosphate (AMP). Both AMP-activated protein kinase (AMPK) and AMPK kinase (AMPKK) are activated by ZMP, which appears to be necessary for the induction of apoptosis. Acadesine-induced apoptosis also appears to require cytochrome c release from mitochondria and caspase activation and is p53-independent. However, the exact mechanism of acadesine-induced apoptosis is unknown. T cells are significantly less susceptible than B cells to acadesine-induced apoptosis. AMPK regulates several cellular systems including the cellular uptake of glucose, the beta-oxidation of fatty acids, protein synthesis, and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  PeriCor Therapeutics; Protherics PLC; Schering-Plough.

According to http://en.wikipedia.org/wiki/Acadesine, acadesine (INN) (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside, AICA-riboside) is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia[2] and may have applications in treating other disorders such as diabetes. Acadesine is an adenosine regulating agent developed by PeriCor Therapeutics and licensed to Schering-Plough in 2007 for phase III studies. The drug is a potential first-in-class agent for prevention of reperfusion injury in CABG surgery. Schering began patient enrollment in phase III studies in May, 2009.

 1: Zhang W, Wang J, Wang H, Tang R, Belcher JD, Viollet B, Geng JG, Zhang C, Wu C, Slungaard A, Zhu C, Huo Y. Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/Akt signaling pathway. Arterioscler Thromb Vasc Biol. 2010 May;30(5):1000-6. Epub 2010 Feb 25.  PubMed PMID: 20185792.

2: Van Den Neste E, Van den Berghe G, Bontemps F. AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies. Expert Opin Investig Drugs. 2010 Apr;19(4):571-8. PubMed PMID: 20367195.

3: Robert G, Ben Sahra I, Puissant A, Colosetti P, Belhacene N, Gounon P, Hofman  P, Bost F, Cassuto JP, Auberger P. Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. PLoS One. 2009 Nov 18;4(11):e7889. PubMed PMID: 19924252; PubMed Central PMCID: PMC2775681.

4: Adamo L, Zhang Y, García-Cardeña G. AICAR activates the pluripotency transcriptional network in embryonic stem cells and induces KLF4 and KLF2 expression in fibroblasts. BMC Pharmacol. 2009 Feb 12;9:2. PubMed PMID: 19216758; PubMed Central PMCID: PMC2651871.

5: Drew BG, Kingwell BA. Acadesine, an adenosine-regulating agent with the potential for widespread indications. Expert Opin Pharmacother. 2008 Aug;9(12):2137-44. Review. PubMed PMID: 18671468.

6: Cronstein BN, Kamen BA. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICA-riboside) as a targeting agent for therapy of patients with acute lymphoblastic leukemia: are we there and are there pitfalls? J Pediatr Hematol Oncol. 2007 Dec;29(12):805-7. PubMed PMID: 18090925.

7: Galardo MN, Riera MF, Pellizzari EH, Cigorraga SB, Meroni SB. The AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleoside, regulates lactate production in rat Sertoli cells. J Mol Endocrinol. 2007 Oct;39(4):279-88. PubMed PMID: 17909267.

8: Cuthbertson DJ, Babraj JA, Mustard KJ, Towler MC, Green KA, Wackerhage H, Leese GP, Baar K, Thomason-Hughes M, Sutherland C, Hardie DG, Rennie MJ. 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes. 2007 Aug;56(8):2078-84. Epub 2007 May 18. PubMed PMID: 17513706.

9: Fukuda T, Ishii K, Nanmoku T, Isobe K, Kawakami Y, Takekoshi K. 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside stimulates tyrosine hydroxylase activity and catecholamine secretion by activation of AMP-activated protein kinase in PC12 cells. J Neuroendocrinol. 2007 Aug;19(8):621-31. PubMed PMID: 17620104.

10: Campàs C, Santidrián AF, Domingo A, Gil J. Acadesine induces apoptosis in B cells from mantle cell lymphoma and splenic marginal zone lymphoma. Leukemia. 2005 Feb;19(2):292-4. PubMed PMID: 15549145.

11: Walker J, Jijon HB, Diaz H, Salehi P, Churchill T, Madsen KL. 5-aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal  glucose transport: a possible role for AMPK. Biochem J. 2005 Jan 15;385(Pt 2):485-91. PubMed PMID: 15367103; PubMed Central PMCID: PMC1134720.

12: Campàs C, Lopez JM, Santidrián AF, Barragán M, Bellosillo B, Colomer D, Gil J. Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes. Blood. 2003 May 1;101(9):3674-80. Epub 2003 Jan 9. PubMed PMID: 12522004.

13: Ragsdale DN, Proctor KG. Acadesine and intestinal barrier function after hemorrhagic shock and resuscitation. Crit Care Med. 2000 Dec;28(12):3876-84. PubMed PMID: 11153629.

14: Nawarskas JJ. Acadesine: a unique cardioprotective agent for myocardial ischemia. Heart Dis. 1999 Sep-Oct;1(4):255-60. PubMed PMID: 11720632.

15: Lasley RD, Randhawa MP Jr, Hegge JO, Mentzer RM. Effects of adenosine and acadesine on interstitial nucleosides and myocardial stunning in the pig. Can J Physiol Pharmacol. 1999 Apr;77(4):259-67. PubMed PMID: 10535674.

16: Melton SM, Moomey CB Jr, Ragsdale DN, Trenthem LL, Croce MA, Fabian TC, Proctor KG. Acadesine during fluid resuscitation from shock and abdominal sepsis. Crit Care Med. 1999 Mar;27(3):565-75. Review. PubMed PMID: 10199538.