AICAR is an AMP-kinase activator widely used in animal research to investigate energy homeostasis and the regulation of metabolism. Studies have found that AICAR can regulate insulin receptors and change muscle cell function, which has led to investigations into its use for the management of diabetes. The molecule has also been found to have anti-cancer properties, slowing the growth of cancer cells both in vivo and in mouse models. It has additionally been used, in the past, to protect heart muscle during surgery1.
What Is AICAR?
AICAR is short for 5-aminoimidazole–4-carboxamide ribonucleoside. It is also called acadesine. It is actually a naturally occurring molecule, acting as an intermediate in the production of other nucleosides. Because it is an intermediate, AICAR is not found in substantial quantities in living organisms.
What makes AICAR so interesting to the research community is that it can penetrate cell walls. Unlike many compounds, it can pass through a cell wall without difficulty and without being altered. That means it is easy to get AICAR to the interior of the cell where it can act to regulate metabolism, cell growth, and cell death.
AICAR in Cancer Research
AICAR is an AMP-kinase activator. AMP-activated protein kinase (AMPK) is very active in cell growth and cell death in almost all animals. It is also thought to play a role in protecting cells against environmental stress2. AICAR can activate AMPK, which has been shown to cause cell death in cancer cells both in vitro and in rats3,4.
AICAR is under investigation as a potential adjunct to chemotherapeutics because it can increase their effectiveness, thus allowing for lower doses of these toxic drugs that cause hair loss, nausea, and worse. AICAR may also be able to play a role in overcoming chemotherapy resistance. After the first round of chemotherapy, there is often a marked increase in the resistance of cancer cells to chemotherapeutic drugs. The current thinking is that AICAR or a similar molecule could slow cancer cell metabolism and make those cells more susceptible to environmental insults and thus less resistant to standard chemotherapy5.
AICAR and Heart Health
Research studies indicates that AICAR may be useful in preventing the progression of vascular diseases, such as atherosclerosis, and thus may be useful in treating diseases that range from heart attack to stroke. Studies in rabbits indicate that the activation of AMPK by AICAR suppresses vascular smooth muscle cell proliferation, an important step in the development of vascular disease. AICAR is being investigated not just as a potential treatment following vascular injury, but as a means to protect against coronary artery disease6.
Current AICAR Research
AICAR is currently being investigated for its ability to impact skeletal muscle growth and is being used to probe deeper into the metabolic pathways of cancer cells. The latter branch of research is using AICAR as a means to dissect cell metabolism and identify potential areas where it might be interrupted in cancer cells.
AICAR is known to boost glucose (blood sugar) uptake in muscle cells7. In type II diabetes, muscle cells often lose their ability to interact with insulin (become insulin resistant) and thus do not respond to signals to take up glucose from the bloodstream. If AICAR can restore some of a muscle’s ability to take up glucose, it could be beneficial in treating diabetes. Much additional research must be conducted to fully understand the benefits and long term effects of AICAR. Many scientists are hopeful that AICAR will serve as the prototype for the development of diabetes drugs in the future.
1. Galiñanes, M., Bullough, D., Mullane, K. M. & Hearse, D. J. Sustained protection by acadesine against ischemia- and reperfusion-induced injury. Studies in the transplanted rat heart. Circulation 86, 589–597 (1992).
2. Corton, J. M., Gillespie, J. G., Hawley, S. A. & Hardie, D. G. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. FEBS 229, 558–565 (1995).
3. Zhuge, J. Overexpression of CYP2E1 induces HepG2 cells death by the AMP kinase activator 5’-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Cell Biol. Toxicol. 25, 253–263 (2009).
4. Rattan, R., Giri, S., Singh, A. K. & Singh, I. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J. Biol. Chem. 280, 39582–39593 (2005).
5. Yung, M. M. H., Ngan, H. Y. S. & Chan, D. W. Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges. Acta Biochim. Biophys. Sin. 48, 301–317 (2016).
6. Igata, M. et al. Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ. Res. 97, 837–844 (2005).
7. Pubchem. AID 389354 – Activation of 5-AMP-induced AMPKalpha in human skeletal muscle cells assessed as Tyr172 phosphorylation at 4 mM relative to control – PubChem. Available at: https://pubchem.ncbi.nlm.nih.gov/bioassay/389354#section=Top. (Accessed: 21st July 2016)