RESUMEN
Colorectal carcinoma is a common malignant tumor occurring in the alimentary system. Despite developments of modern medicine, developed resistance to 5-fluorouracil (5-FU) may lead to poor prognosis. Herein, we aimed to explore the effects of beta-elemene on colorectal carcinoma cells (HCT116 and HT29) as well as the underlying mechanisms. Beta-elemene reduced cell viability and induced apoptosis in HCT116 and HT29 cells. Increased apoptosis following beta-elemene exposure was due to enhanced sensitivity to 5-FU through down-regulating miR-191. Expression of key kinases, including Wnt3a, and ß-catenin, were down-regulated by beta-elemene through a miR-191 mechanism. Moreover, beta-elemene might improve resistance of colorectal carcinoma cells to 5-FU by down-regulating miR-191, thereby inhibiting the Wnt/ß-catenin pathway.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Regulación hacia Abajo/efectos de los fármacos , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/biosíntesis , ARN Neoplásico/biosíntesis , Sesquiterpenos/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Fluorouracilo/agonistas , Células HCT116 , Humanos , MicroARNs/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Sesquiterpenos/agonistas , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt3A/biosíntesis , Proteína Wnt3A/genética , beta Catenina/biosíntesis , beta Catenina/genéticaRESUMEN
Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antifúngicos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/enzimología , Piridonas/farmacología , Sesquiterpenos/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/agonistas , Antifúngicos/agonistas , Línea Celular Tumoral , Ciclopirox , Sinergismo Farmacológico , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Piridonas/agonistas , Sesquiterpenos/agonistas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The Drosophila malate dehydrogenase, or malic enzyme (ME) encoded by the Men gene, is a non-mitochondrial enzyme recovered in the cytosolic fraction. By using mutation in the Men gene and deficiencies uncovering this locus, we could show that the ME activity recovered in cytosolic fractions originates exclusively from the Men gene located at map position 87D-1 on the right arm of the 3rd chromosome. We found that juvenile hormone (JH) can induce ME activity by two mechanisms. One mechanism corresponds to a direct effect of JH on the enzyme, whose activity was enhanced by a twofold factor in the absence of transcription and translation. This enhancement can be noticed 1 h after JH treatment and lasts for approx 3-4 h. The other mechanism involves the transcription of the MEN gene. In the absence of inhibitors the induction of ME activity by JH is increased by a three to fourfold factor and extends over a period of 10-16 h. Since induction of ME activity by JH and JH analogs displayed a dose-response curve, specific for each tested component, we concluded that the hormonal action could be mediated through a receptor. The use of two temperature sensitive mutations deficient in the production of ecdysteroid, ecd1 and su(f)ts67g revealed that ME response to JH requires the presence of a minimal level of the steroid hormone ecdysone, showing a complex hormonal regulatory circuit in the execution of the JH response.