RESUMEN
PURPOSE: Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B. METHODS: Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting. RESULTS: In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on human cancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway. CONCLUSIONS: These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Compuestos de Bifenilo/farmacología , Epotilonas/farmacología , Neoplasias/tratamiento farmacológico , Nitrofenoles/farmacología , Sulfonamidas/farmacología , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Epotilonas/administración & dosificación , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Nitrofenoles/administración & dosificación , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazinas/administración & dosificación , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfonamidas/administración & dosificación , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti-proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib.