Combination therapy with 5-amino-4-imidazolecarboxamide riboside and arsenic trioxide in acute myeloid leukemia cells involving AMPK/TSC2/mTOR pathway
Department of Pediatrics, the Second Affiliated Hospital of Harbin Medical University, Harbin, China. Pharmazie
(Impact Factor: 1.05).
02/2013; 68(2):117-23. DOI: 10.1691/ph.2013.2666
The aim of this study was to demonstrate the effects of the AMP-activated protein kinase (AMPK) activator 5-amino-4-imidazolecarboxamide riboside (AICAR) in combination with arsenic trioxide (ATO) in acute myeloid leukemia cells and determine its mechanism of action. Cell lines were either exposed to each drug alone or both the drugs simultaneously. Cell proliferation, cell cycle and apoptosis were assessed. Combination index (CI) method was used to calculate the synergistic, additive, or antagonistic effects of these drugs. Western blot technique was used to study the signaling molecules in the AMPK/TSC2/mTOR pathway. Simultaneous exposure of HL-60 cells to AICAR and ATO indicated a synergism (CI < 1), whereas CI on NB4 cells was greater than 1. In HL-60, the change in expression level of each protein was quite significant in the presence of the combination as compared to that induced through any single agent. On the contrary, ATO weakened the effect of AICAR-mediated AMPK activation in NB4 cells. ATO caused a profound decrease in the protein level of PML/RARalpha in NB4 cells after 48 h, but there was no change with AICAR and the combination. The combination of AICAR and ATO produced a synergistic effect in the treatment of HL-60 cells involving AMPK/TSC2/mTOR pathway, and AICAR reduced ATO-mediated apoptotic death on acute promyelocytic leukemia NB4 cells.
Available from: Luca Laurenti
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ABSTRACT: Autoimmune cytopenias are a frequent complication in CLL, occurring in approximately 5–10% of the patients. The most common manifestation is autoimmune haemolytic anaemia, followed by immune thrombocytopenia and only rarely pure red blood cell aplasia or autoimmune granulocytopenia. Initial treatment is as for the idiopathic autoimmune cytopenias, with most patients responding to conventional corticosteroid therapy. Patients, who do not respond to conventional therapy after 4–6 weeks, should be considered for alternative immunosuppression, monoclonal antibody therapy or splenectomy. While randomized trials demonstrating the benefit of rituximab in CLL-related autoimmune diseases are still lacking, there are considerable data in the literature that provide evidence for its effectiveness.
The monoclonal antibody alemtuzumab also displays considerable activity against both the malignant disease and the autoimmune complication in patients with CLL, although at the expense of greater toxicity. A number of new monoclonal antibodies, such as ofatumumab, GA-101, lumiliximab, TRU-016, epratuzumab, and galiximab, are currently investigated in CLL and their activity in CLL-related autoimmune cytopenias should be evaluated in future studies.
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ABSTRACT: The combination of fenretinide and selenite on ovarian cancer cells was investigated to assess its effects on proliferation and ability to induce apoptosis. Our results showed that fenretinide and selenite in combination significantly suppress the proliferation of ovarian cancer cells and induced apoptosis (including reactive oxygen species generation, and the loss of mitochondrial membrane potential) compared with either drug used alone. The caspase3/9-dependent pathway was triggered significantly in combination treatment, and moreover, the AMPK pathway also mediated the apoptosis induction in fenretinide and selenite combination. Fenretinide and selenite combination treatment was demonstrated to suppress tumor growth in vivo, this drug combination has been thus found to have an enhanced anti-tumor effect on ovarian cancers cells.
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