RESUMEN
Zoledronic acid (ZOL) was shown earlier to prolong survival in animal models of lung cancer. The aim of this study was to examine whether alteration of intracellular cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, retinoblastoma, and Ras protein expression and E2F localization are among the possible antilung cancer mechanisms driven by ZOL. Furthermore, we used geranylgeraniol to test whether the mevalonate pathway is involved in the antitumor effects of ZOL against lung cancer. Line-1 cells, a murine lung adenocarcinoma cell line, were examined. ZOL significantly slowed the growth of these cells both in vitro and in vivo. The ZOL-treated cells typically arrested at the S/G2/M phase of the cell cycle, accompanied by increased intracellular levels of cyclin A, B1, and CDC2 and decreased levels of cyclin D, p21, p27, phosphorylated retinoblastoma, and Ras. In addition, ZOL affected the distribution of E2F. When geranylgeraniol was added to the ZOL-treated cells, either in vitro or in vivo, tumor growth, cell-cycle progression, the expression of certain cyclins, and cyclin-related regulatory proteins were partially returned to that of untreated controls. Therefore, ZOL elicits cell-cycle prolongation that seems to be associated with alterations in the levels of certain cyclins and cyclin-related regulatory proteins. Furthermore, the mevalonate pathway regulates ZOL-induced murine lung cancer inhibition both in vitro and in vivo.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Ciclinas/biosíntesis , Difosfonatos/farmacología , Imidazoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas ras/biosíntesis , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Quinasas Ciclina-Dependientes/biosíntesis , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/genética , Difosfonatos/antagonistas & inhibidores , Diterpenos/farmacología , Regulación hacia Abajo/efectos de los fármacos , Factores de Transcripción E2F/metabolismo , Imidazoles/antagonistas & inhibidores , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ácido Mevalónico/metabolismo , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Proteína de Retinoblastoma/metabolismo , Ácido Zoledrónico , Proteínas ras/antagonistas & inhibidores , Proteínas ras/genéticaRESUMEN
Strain CC-SAL-25(T), a non-motile, Gram-negative, red-pigmented bacterium, was isolated from a rare mud-volcano, located in Wandan, Pingtung County, Taiwan. Studies based on 16S rRNA gene sequences showed that the strain clustered closely with Belliella baltica BA143(T) (95.4 % sequence similarity). A menaquinone with seven isoprene units (MK-7) was the major respiratory quinone. The fatty acid profile was slightly different from that of B. baltica BA143(T). The results of the physiological and biochemical tests showed that strain CC-SAL-25(T) could be clearly differentiated from recognized Belliella species based on phenotypic properties. It was evident from the genotypic and phenotypic data that strain CC-SAL-25(T) should be classified as representing a second novel species in the genus Belliella. The name proposed for this taxon is Belliella pelovolcani sp. nov., and the type strain is CC-SAL-25(T) (=BCRC 17883(T)=KCTC 13248(T)).