AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies

• Published in: Expert opinion on investigational drugs Vol. 19; no. 4; p. 571
• Main Authors: Van Den Neste, Eric, Van den Berghe, Georges, Bontemps, Françoise
• Format: Journal Article
• Language: English
• Published: England 01.04.2010
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Aminoimidazole Carboxamide - therapeutic use; AMP-Activated Protein Kinases - metabolism; Animals; Clinical Trials as Topic - trends; Enzyme Activation - drug effects; Enzyme Activation - physiology; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - enzymology; Humans; Ribonucleosides - pharmacology; Ribonucleosides - therapeutic use
• ISSN: 1744-7658
• DOI: 10.1517/13543781003703694

Despite considerable advances, B-cell chronic lymphocytic leukemia (CLL) is incurable with standard approaches. Thus, there remains a need for new therapies, particularly for patients who develop chemoresistance to DNA-targeting treatments. AICA-riboside (acadesine) is a nucleoside with a wide range of metabolic effects, including release of adenosine and activation of AMP-activated protein kinase (AMPK), which was initially developed as a cardioprotective agent. More recently, it has been shown that AICA-riboside induces apoptosis in various models of leukemia, including CLL. The literature data show that apoptosis induced by AICA-riboside in CLL is not dependent on a functionally normal p53 pathway. Moreover, AICA-riboside is active towards resting and proliferative models of leukemia cells, including resistant phenotypes. Finally, studies in healthy subjects and during coronary artery bypass graft surgery show that AICA-riboside is devoid of serious toxicity. This paper reviews the mechanisms of action of AICA-riboside in normal and malignant cells and discusses how AICA-riboside could impact CLL treatment. We propose that AICA-riboside, which displays a relative selectivity and a favorable toxicity profile, may offer a new treatment option for CLL.