Figure 10

Proposed mechanism of action for AICAR in human leukemia ALL cells. After crossing the cell membrane, AICAR is metabolized by the adenosine kinase (AK) to its active mono-phosphorylated form ZMP (AMP analogue) which activates AMPK. The activated AMPK will signal to multiple downstream targets impinging on cell growth, cell proliferation, and cell survival. In ALL cells, induction of AMPK by AICAR increases the levels of p53, the cdk inhibitor p27, and the p38-MAPK leading to inhibition of cell proliferation, cell arrest in G1-phase, and apoptosis. In addition, P-AMPK activates TSC2 reducing the level of mTOR, an important regulatory factor of the PI3K/Akt pathway necessary for cell proliferation [24]. As a cell survival mechanism, the level of Akt is increased to overcome the reduction in mTOR attempting to restore or promote cell growth. AICAR, 5-Aminoimidazole-4-Carboxamide-1-β-4-Ribofuranoside; AK, adenosine kinase; AMPK, AMP activated protein kinase; PI3K, phosphatidylinositol 3-kinase; Akt, proteinase kinase B; TSC, tuberous sclerosis complex; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase.