Abstract
Background:
Inhibition of signal transduction pathways has been successfully introduced into cancer treatment. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 has antitumor activity in vitro against solid tumors. Here, we examined the activity of NVP-BEZ235 in acute lymphoblastic leukemia (ALL) cells and the best modalities for combination approaches.
Materials and methods:
ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were treated with NVP-BEZ235 alone, or in combination with cytarabine (AraC), doxorubicin (Doxo) or dexamethasone (Dexa).
Results:
NVP-BEZ235 potently inhibited the proliferation and metabolic activity of ALL cells. Antiproliferative effects were associated with G(0)/G(1) arrest and reduced levels of cyclin-dependent kinase 4 (CDK4) and cyclin D3. Inhibition of PI3K and mTOR activity was detected at 10 and 100 nM. NVP-BEZ235 combined with AraC, Doxo or Dexa synergistically enhanced the cytotoxicity compared to single-drug treatment, even in glucocorticoid-resistant cells.
Conclusion:
NVP-BEZ235 displays pronounced antiproliferative effects in ALL cells and might therefore be a useful drug in the treatment of ALL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Cytarabine / administration & dosage
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Dexamethasone / administration & dosage
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Doxorubicin / administration & dosage
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Drug Resistance, Neoplasm
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Drug Synergism
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology*
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Jurkat Cells
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Leukemia, B-Cell / drug therapy
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Leukemia, B-Cell / enzymology
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Leukemia, B-Cell / metabolism
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Leukemia, B-Cell / pathology
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Oncogene Protein v-akt / antagonists & inhibitors
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Oncogene Protein v-akt / metabolism
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Quinolines / administration & dosage
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Quinolines / pharmacology*
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Signal Transduction
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
Substances
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Quinolines
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Cytarabine
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Dexamethasone
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Doxorubicin
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MTOR protein, human
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Phosphatidylinositol 3-Kinase
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Oncogene Protein v-akt
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TOR Serine-Threonine Kinases
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dactolisib