RESUMEN
Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.
Asunto(s)
Compuestos de Anilina , Antineoplásicos/farmacología , Benzamidas , Benzodiazepinonas , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Nitrilos , Piperazinas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Proteínas Quinasas/metabolismo , Pirazoles , Pirimidinas , Quinolinas , Sustitución de Aminoácidos , Compuestos de Anilina/agonistas , Compuestos de Anilina/farmacología , Animales , Benzodiazepinonas/agonistas , Benzodiazepinonas/farmacología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , MAP Quinasa Quinasa 1/genética , MAP Quinasa Quinasa 1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Desnudos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mutación Missense , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Nitrilos/agonistas , Nitrilos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pirazoles/agonistas , Pirazoles/farmacología , Quinolinas/agonistas , Quinolinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To investigate the putative mediation of peripheral benzodiazepine receptor (PBR) in the cytotoxicity of flavonoids, in this study, modulatory effects of several flavonoids on the lipid peroxide (LPO) production and PBR mRNA expression of human neuroblastoma cells were observed. Elevated levels of peroxidated products in cancer cells may activate pro-apoptotic and anti-proliferative signaling pathways. Treatment of 10(-6) M 4'-chlorodiazepam and PK 11195 ligands of the PBR for 6 days enhanced the generation of LPO of the human neuroblastoma cells. Several flavonoids, well-known cytotoxic substances, potentiated the enhancement of LPO production by PBR ligands. Treatment of 10(-6) M flavonoids for 6 days elevated the expression of PBR mRNA in cells. These findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their PBR-inducing properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and anti-neoplastic effects.