Abstract
A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH(2)-terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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BH3 Interacting Domain Death Agonist Protein / metabolism
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Blotting, Western
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Caspases / metabolism*
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Cell Survival / drug effects
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Cytochromes c / metabolism
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Down-Regulation
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Electrophoretic Mobility Shift Assay
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Enzyme Activation
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Flow Cytometry
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Humans
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Immunoenzyme Techniques
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Leukemia-Lymphoma, Adult T-Cell / metabolism
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Leukemia-Lymphoma, Adult T-Cell / pathology*
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Membrane Microdomains / metabolism
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Mitochondria / drug effects
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Mitochondria / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylcholine / analogs & derivatives*
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Phosphorylcholine / pharmacology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Tumor Cells, Cultured
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Vinblastine / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents, Phytogenic
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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RNA, Messenger
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RNA, Small Interfering
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Phosphorylcholine
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perifosine
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Vinblastine
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Cytochromes c
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Caspases