Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine.
The mammalian target of rapamycin (mTOR) kinase is a key regulator of cell growth and proliferation. Overexpression of the mTOR signaling pathway has been described in several tumor cells, including the majority of acute myeloid leukemia (AML) cases. The anti-tumor efficacy of mTOR inhibitors was shown in several preclinical and clinical studies. In AML, however, the potential antineoplastic effect of mTOR inhibitors has received little attention thus far. In this in-vitro study of the human AML cell line, HL-60, we aimed to assess the antileukemic activity of rapamycin (RAPA), an mTOR inhibitor, alone and in combination with cytarabine (Ara-C). The study showed that RAPA in concentrations of 1-10 nmol/l arrested the cell cycle progression of Hl-60 cells in the G1 phase, without evident cytotoxic effect. This effect was associated with significant inhibition of cyclin E expression. At concentrations higher than 10 nmol/l, RAPA exerted a significant proapoptotic effect, with the collapse of mitochondrial potential and caspase-3 activation. The most prominent proapoptotic effect was observed for a combination of 1 nmol/l of RAPA and 50 nmol/l of Ara-C, especially when Ara-C was added at a 24-h interval after RAPA. In conclusion, these data indicate that RAPA might be effective in the treatment of acute leukemia patients, especially in combination with Ara-C, the drug routinely used in AML treatment. On the basis of these results, attempts to combine classical induction chemotherapy with an inhibitor of the mTOR kinase in AML treatment could be warranted.
Janus
Agnieszka
A
Departments of aHematology bExperimental Hematology, Medical University of Lodz, Poland.
Linke
Anna
A
Cebula
Barbara
B
Robak
Tadeusz
T
Smolewski
Piotr
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D016213:Cyclins / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002867:Chromones; D016213:Cyclins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D003561:Cytarabine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D020123:Sirolimus