RESUMO
p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.
Assuntos
Humanos , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , /metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/farmacologia , Antineoplásicos/farmacologia , Benzamidas/metabolismo , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , /efeitos dos fármacos , /metabolismo , /genética , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Regulação para Baixo/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , /efeitos dos fármacos , /metabolismo , Pirimidinas/metabolismo , /efeitos dos fármacosRESUMO
No abstract available.