RESUMEN
To investigate the combined effects of indomethacin and oxaliplatin on expressions of epidermal growth factor receptor (EGFR), E-cadherin (E-cad), intercellular adhesion molecule-1 (ICAM-1) and CD44v6 related to lymph node metastasis of human lung cancer cell lines. Human lung adenocarcinoma A549 cells were inoculated subcutaneously into the left armpit of nude mice to establish human lung cancer xenografts. The mice were randomly divided into control group, indomethacin group, oxaliplatin group and combination therapy group, which were treated with sterile distilled water, indomethacin, oxaliplatin and indomethacin combined with oxaliplatin, respectively. After 42 days, the mice were sacrificed. The immunohistochemistry and reverse transcription polymerase chain reaction were used to detect the expressions of EGFR, E-cad, ICAM-1 and CD44v6 in tumor tissues. Compared to control group, the protein and mRNA expressions of EGFR, ICAM-1 and CD44v6 in the indomethacin, oxaliplatin, and combination therapy groups were significantly reduced (P<0.05) and the protein and mRNA expressions of E-cad expression were significantly increased (P<0.05). Compared to indomethacin group and oxaliplatin group, the protein and mRNA expressions of EGFR, ICAM-1 and CD44v6 in combination therapy groups were significantly reduced (P<0.05), and the protein and mRNA expressions of E-cad expression were significantly increased (P<0.05). There was no significant difference between indomethacin and oxaliplatin groups. Indomethacin and oxaliplatin have synergistic effect on expressions of lymph node metastasis related factors in lung cancer cell lines.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Indometacina/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Células A549 , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adenocarcinoma del Pulmón , Animales , Antígenos CD , Cadherinas/genética , Cadherinas/metabolismo , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Oxaliplatino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: This study was designed to evaluate the inhibitory effect of nimesulide in combination with oxaliplatin on tumor growth, expression of COX-2, VEGF-C, VEGFR-3, survivin and ß-catenin, and lymphatic metastasis in lung cancer xenograft in nude mice, and to discuss the possible synergistic effect of nimesulide in combination with oxaliplatin. METHODS: Human lung cancer A549 cells were injected into BALB/c nude mice subcutaneously. Thirty-three healthy male nude mice were randomly divided into 4 groups: the control group, nimesulide group, oxaliplatin group and nimesulide combined with oxaliplatin group. Transplanted tumor tissues were collected and the expressions of COX-2, VEGF-C, VEGFR-3, survivin, ß-catenin protein were detected by immunohistochemistry, and RT-PCR assay was used to assess the expression of tumor COX-2, VEGF-C, VEGFR-3, survivin and ß-catenin mRNA. SPSS 16.0 was used for statistical analysis. Data were present as (x(-) ± s), and the means were compared by analysis of variance test. RESULTS: Tumor inhibition rates of the nimesulide group, oxaliplatin group and nimesulide + oxaliplatin group were 39.73%, 48.04% and 65.94%, respectively. Immunohistochemical and RT-PCR analysis showed that compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and ß-catenin of the nimesulide group were significantly reduced (all P < 0.05). Compared with the control group, statistical analysis of variance showed that the expression levels of COX-2, VEGF-C and VEGFR-3 of the oxaliplatin group were significantly increased (P < 0.05), the expression levels of survivin and ß-catenin protein and mRNA of the oxaliplatin group were significantly reduced (P < 0.05). Compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and ß-catenin of the nimesulide + oxaliplatin group were significantly reduced (all P < 0.05). CONCLUSIONS: Both nimesulide alone or in combination with oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice and the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and ß-catenin. Oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice, and the expression of survivin and ß-catenin. Nimesulide in combination with oxaliplatin enhances the antitumor effect of oxaliplatin.