Abstract
Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is aberrantly activated in acute myeloid leukemia (AML) patients, where it contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, inhibiting mTOR signaling in AML blasts could enhance their sensitivity to cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition with rapamycin impaired leukemia initiating cells (LICs) function. In this study, we assessed the therapeutic potential of a combination consisting of temsirolimus [an allosteric mTOR complex 1 (mTORC1) inhibitor] with clofarabine, a nucleoside analogue with potent inhibitory effects on both ribonucleotide reductase and DNA polymerase. The drug combination (CLO-TOR) displayed synergistic cytotoxic effects against a panel of AML cell lines and primary cells from AML patients. Treatment with CLO-TOR induced a G₀/G₁-phase cell cycle arrest, apoptosis, and autophagy. CLO-TOR was pro-apoptotic in an AML patient blast subset (CD34⁺/CD38⁻/CD123⁺), which is enriched in putative leukemia initiating cells (LICs). In summary, the CLO-TOR combination could represent a novel valuable treatment for AML patients, also in light of its efficacy against LICs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase 1 / metabolism
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Adenine Nucleotides / pharmacology
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Allosteric Regulation
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Antigens, CD34 / metabolism
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Antimetabolites, Antineoplastic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Arabinonucleosides / pharmacology
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Autophagy / drug effects
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Cell Line, Tumor
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Clofarabine
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Dose-Response Relationship, Drug
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Drug Synergism
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Eukaryotic Initiation Factor-4F / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Interleukin-3 Receptor alpha Subunit / metabolism
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / enzymology
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Leukemia, Myeloid, Acute / immunology
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Leukemia, Myeloid, Acute / pathology
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Membrane Glycoproteins / metabolism
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-myc / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Sirolimus / analogs & derivatives
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Tumor Cells, Cultured
Substances
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Adenine Nucleotides
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Antigens, CD34
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Antimetabolites, Antineoplastic
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Arabinonucleosides
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Eukaryotic Initiation Factor-4F
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IL3RA protein, human
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Interleukin-3 Receptor alpha Subunit
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MYC protein, human
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Membrane Glycoproteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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STAT3 Transcription Factor
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STAT3 protein, human
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temsirolimus
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Clofarabine
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MTOR protein, human
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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CD38 protein, human
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ADP-ribosyl Cyclase 1
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Sirolimus