RESUMO
Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/patologia , Camundongos Endogâmicos NOD , Camundongos SCID , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Carga Tumoral/efeitos dos fármacosRESUMO
Ionotropic neurotransmitter receptors mediate rapid synaptic transmission in the CNS and PNS. Owing to this central role in trans-synaptic signal transduction, modulation of these receptors could play a crucial role in the expression of synaptic plasticity in the brain. AMPA receptors mediate the majority of rapid excitatory synaptic transmission in the CNS. Recent studies have indicated that the activity and synaptic distribution of these receptors is dynamically regulated and could be crucial for the short- and long-term modification of synaptic efficacy. Here we review recent data on the molecular mechanisms that underlie the modulation of AMPA receptors and the role of AMPA-receptor regulation in mediating synaptic plasticity.
