RESUMO
Drug resistance remains a major hurdle to successful cancer treatment. Many mechanisms such as overexpression of multidrug-resistance related proteins, increased drug metabolism, decreased apoptosis, and impairment of signal transduction pathway can contribute multidrug resistance (MDR). Recent studies strongly suggest a close link between cytokines and drug resistance. To identify new targets involved in drug resistance, we established a multidrug-resistant human breast cancer cell line MCF-7/R and examined the cytokine profile using cytokine antibody array technology. Among 120 cytokines/chemokines screened, IL-6, IL-8, and 13 other proteins were found to be markedly increased in drug-resistant MCF-7/R cell line as compared to sensitive MCF-7/S cell line, while 7 proteins were specifically reduced in drug-resistant MCF-7/R cells. Neutralizing antibodies against IL-6 and IL-8 partially reversed the drug resistance of MCF-7/R to paclitaxel and doxorubicin, while a neutralizing antibody against MCP-1 had no significant effect. Inhibition of endogenous IL-6 or IL-8 by siRNA technology significantly enhanced drug sensitivity of MCF-7/R cells. Furthermore, overexpression of IL-6 or IL-8 expression by transfection increased the ADM resistance in MCF-7/S cells. Our data suggest that increased expression levels of IL-6 and IL-8 may contribute to MDR in human breast cancer cells.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Sequência de Bases , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Células MCF-7 , Dados de Sequência Molecular , Paclitaxel/farmacologia , RNA Interferente Pequeno , Receptores de Interleucina-6/genética , Receptores de Interleucina-8/genéticaRESUMO
Two new degraded limonoids, azedararide and 12alpha-acetoxy fraxinellone, were isolated together with two known degraded limonoids, fraxinellone and fraxinellonone, as ichthyotoxic substances from the root bark of Melia azedarach. Their structures were elucidated by spectroscopic and chemical means.
