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Cell Physiol Biochem ; 36(3): 893-906, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26065336

RESUMO

BACKGROUND: Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity. METHODS: In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity' colony formation' TUNEL staining' flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism. RESULTS: It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells. CONCLUSION: Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Cumarínicos/farmacologia , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais
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