sirolimus and acadesine

Differentiation therapy of acute promyelocytic leukemia with all-trans retinoic acid represents the most successful pharmacological therapy of acute myeloid leukemia (AML). Numerous studies demonstrate that drugs that inhibit mechanistic target of rapamycin (mTOR) and activate AMP-kinase (AMPK) have beneficial effects in promoting differentiation and blocking proliferation of AML. Most of these drugs are already in use for other purposes; rapalogs as immunosuppressants, biguanides as oral antidiabetics, and 5-amino-4-imidazolecarboxamide ribonucleoside (AICAr, acadesine) as an exercise mimetic. Although most of these pharmacological modulators have been widely used for decades, their mechanism of action is only partially understood. In this review, we summarize the role of AMPK and mTOR in hematological malignancies and discuss the possible role of pharmacological modulators in proliferation and differentiation of leukemia cells.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Clinical Trials as Topic; Humans; Leukemia, Myeloid, Acute; Metformin; Ribonucleosides; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Two muscle-specific ubiquitin ligases (UL), muscle atrophy F box (MAFbx) and muscle RING finger 1 (MuRF1), are crucial for myofibrillar protein breakdown. The insulin like growth factor-1 (IGF-1) pathway inhibits muscle UL expression through Akt-mediated inhibition of FoxO transcription factors, while AMP-activated protein kinase (AMPK) promotes UL expression. The underlying cellular mechanism, however, remains obscure. In this study, the effect of AMPK and its interaction with IGF-1 on ubiquitin ligases expression was investigated. C2C12 myotubes were treated with 0, 0.1, 0.3, and 1.0 mM 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) in the presence or absence of 50 ng/ml IGF-1. IGF-1 activated Akt, which enhanced phosphorlytion of FoxO3a at Thr 318/321 and reduced the expression of UL. Intriguingly, though activation of AMPK by 0.3 and 1.0 mM AICAR synergized IGF-1-induced Akt activation, the expression of UL was not attenuated, but strengthened by AMPK activation. AICAR treatment decreased FoxO3a phosphorylation at 318/321 in the cytoplasm and induced FoxO3 nuclear relocation. mTOR inhibition increased basal MAFbx expression and reversed the inhibitory effect of IGF-1 on UL expression. In conclusion, our data show that AMPK activation by AICAR stimulates UL expression despite the activation of Akt signaling, which may be due to the possible antagonistic effect of FoxO phosphorylation by AMPK on phosphorylation by Akt. In addition, AMPK inhibition of mTOR may provide an additional explanation for the enhancement of UL expression by AMPK.

Topics: Acetyl-CoA Carboxylase; Adaptor Proteins, Signal Transducing; Adenosine Monophosphate; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Carrier Proteins; Cell Cycle Proteins; Cell Differentiation; Cell Line; Dose-Response Relationship, Drug; Eukaryotic Initiation Factors; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation, Enzymologic; Insulin-Like Growth Factor I; Mice; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Phosphoprotein Phosphatases; Phosphoproteins; Phosphorylation; Protein Kinases; Protein Transport; Proto-Oncogene Proteins c-akt; Ribonucleosides; Signal Transduction; Sirolimus; SKP Cullin F-Box Protein Ligases; TOR Serine-Threonine Kinases; Tripartite Motif Proteins; Ubiquitin-Protein Ligases