Background
AICAR (also called acadesine) is a purine nucleoside. Three pharmacological applications of AICAR were identified: i) stimulation under ischemic conditions of the cardiac production of the vasodilator, adenosine [1]; ii) inhibition of hepatic gluconeogenesis at the level of fructose-1,6-bisphosphatase [2], of therapeutic potential in diabetes; and iii) stimulation of AMP-activated protein kinase (AMPK), initially applied to inhibit the hepatic synthesis of triglycerides and cholesterol [3].
AICAR (treated 48 hours) inhibited cell proliferation of mantle cell lymphoma (MCL) cell lines, REC-1, JEKO-1, UPN-1, JVM-2, MAVER-1 and Z-138, with IC50s of 0.28, 0.59, 0.64, 0.98, 0.50, and 0.14 Mm respectively [4]. AICAR inhibited the growth and depletion of pyrimidine nucleotide pools in fibroblasts [5], accelerated repletion of purine nucleotide pools in heart [6], inhibition of fatty acid, sterol synthesis, and gluconeogenesis in hepatocytes, and increase in glucose uptake in muscle [7].
AICAR (500 mg/kg) injected intraperitoneally into C57BL/6J mice 1 hour before LPS administration. LPS induced the expression of TF mRNA in many major organs, including the lung and liver [8]. A daily administration of 400mg/kg AICAR in mice previously inoculated with a MCL xenotransplant significantly reduced tumor burden when compared to control animals, as soon as 7 days of treatment [9].
参考文献:
[1]. Gruber H E, Hoffer M E, McAllister D R, et al. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury[J]. Circulation, 1989, 80(5): 1400-1411.
[2]. Vincent M F, Marangos P J, Gruber H E, et al. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes[J]. Diabetes, 1991, 40(10): 1259-1266.
[3]. Hardie D G, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?[J]. Annual review of biochemistry, 1998, 67: 821.
[4]. Montraveta A, Xargay-Torrent S, López-Guerra M, et al. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma[J]. Oncotarget, 2014, 5(3): 726.
[5]. Sabina R L, Patterson D, Holmes E W. 5-Amino-4-imidazolecarboxamide riboside (Z-riboside) metabolism in eukaryotic cells[J]. Journal of Biological Chemistry, 1985, 260(10): 6107-6114.
[6]. Swain J L, Hines J J, Sabina R L, et al. Accelerated repletion of ATP and GTP pools in postischemic canine myocardium using a precursor of purine de novo synthesis[J]. Circulation Research, 1982, 51(1): 102-105.
[7]. Hardie D G, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?[J]. Annual review of biochemistry, 1998, 67: 821.
[8]. Zhang W, Wang J, Wang H, et al. Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/Akt signaling pathway[J]. Arteriosclerosis, thrombosis, and vascular biology, 2010, 30(5): 1000-1006.
[9]. Montraveta A, de Fri?as M, Campa?s C, et al. The Nucleoside Analogue Acadesine Exerts Antitumoral Activity and Cooperates with Conventional Agents In In Vitro and In Vivo Models of Mantle Cell Lymphoma[J]. Blood, 2010, 116(21): 3918.
AICAR（也称为 acadesine）是一种嘌呤核苷。确定了 AICAR 的三种药理学应用:i) 在缺血条件下刺激心脏产生血管扩张剂腺苷 [1]； ii) 在 fructose-1,6-bisphosphatase [2] 水平抑制肝糖异生，具有治疗糖尿病的潜力； iii) 刺激 AMP 活化蛋白激酶 (AMPK)，最初用于抑制肝脏合成甘油三酯和胆固醇[3]。
AICAR（处理 48 小时）抑制套细胞淋巴瘤 (MCL) 细胞系 REC-1、JEKO-1、UPN-1、JVM-2、MAVER-1 和 Z-138 的细胞增殖，IC50 为 0.28 , 0.59, 0.64, 0.98, 0.50, 0.14 Mm [4]。 AICAR 抑制成纤维细胞 [5] 中嘧啶核苷酸库的生长和消耗，加速心脏中嘌呤核苷酸库的补充 [6]，抑制脂肪酸、甾醇合成，和肝细胞中的糖异生，以及肌肉中葡萄糖摄取的增加[7]。
AICAR (500 mg/kg) 在 LPS 给药前 1 小时腹膜内注射到 C57BL/6J 小鼠中。 LPS 在许多主要器官中诱导 TF mRNA 的表达，包括肺和肝[8]。与对照动物相比，在预先接种 MCL 异种移植物的小鼠中每天给予 400 毫克/千克 AICAR，只要治疗 7 天[9]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Nine human MCL cell lines (GRANTA-519, JVM-2, JEKO-1, Z-138, MAVER-1, REC-1, UPN-1, HBL-2 and MINO)
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Preparation Method
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MCL cell lines were incubated with AICAR at doses ranging from 0.1 to 2 mM for 24 or 48 hours.
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Reaction Conditions
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0.1 to 2 mM for 24 or 48 hours.
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Applications
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Most of the cell lines analyzed (REC-1, JEKO-1, UPN-1, JVM-2, MAVER-1 and Z-138) showed a IC50 lower than 1 mM after 48 hours of acadesine incubation.
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| Animal experiment [2]: |
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Animal models
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Female Nude NMRI Mice
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Preparation Method
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Mice were randomized into two experimental groups, each containing 15 animals. Animals in both groups received a 100 μl injection of 5*106 K562 leukemia cells on both flanks. When tumors reached 150-200 mm3, animals were injected intraperitoneally with NaCl 0.9% or AICAR at dose level of 50 mg/kg body weight.
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Dosage form
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Intraperitoneal injection, 0, 0.25, 0.5, 1 or 2 mg
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Applications
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AICAR significantly reduced tumor formation in nude mice. Statistical analysis of tumor size shows a robust reduction of 68% at day 16 and 51% at day 20.
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参考文献:
[1]: Montraveta A, Xargay-Torrent S, López-Guerra M, et al. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma[J]. Oncotarget, 2014, 5(3): 726.
[2]: Robert G, Ben Sahra I, Puissant A, et al. Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death[J]. PloS one, 2009, 4(11): e7889.
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