RESUMEN
The aim of this study was to evaluate the anticancer and antitumor activities of ceramide analog 315 in nude mice. Nude mice (n=10) were injected bilaterally with 5×10 MDA-MB-231 cells on each side. Tumors were allowed to form for 2 weeks. The mice were then divided into two groups (n=5 in each group). The control group mice were injected with 25 µl of dimethyl sulfoxide and the treatment group mice were injected with 10 mg/kg of analog 315 (in dimethyl sulfoxide, 25 µl volume) every day for a period of 3 weeks. Animal weights and tumors were measured every week for 3 weeks. At the end of the experimental period, control animals had retained excess fluid, and showed larger tumor sizes compared with the treated group (2.95 vs. 1.67 g). A 45% reduction in tumor size and 80% decrease in tumor volume were observed in the treatment group. There was a significant increase in the weights of liver (10%) and spleen (19%) between the control and treated animals. Hematoxylin and Eosin staining of MDA-MB-231 tumor sections revealed more acellular necrotic regions in tumors from the treatment groups compared with the ones from the control group. Ki67, a proliferation marker was higher in number in control tumor section (71.8±12.8) compared to the treatment tumor section (37.4±10.4) (P<0.001). Photomicrographs showed metastatic tumor burden in kidney, lungs, and spleen collected from the control group mice bearing MDA-MB-231 tumors. Treatment group mice showed normal microscopic tissue architecture. Overall, our study showed tumor growth inhibition and antimetastatic effects for the novel ceramide analog 315.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ceramidas/farmacología , Carga Tumoral/efectos de los fármacos , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ceramidas/química , Dimetilsulfóxido/administración & dosificación , Femenino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Renales/prevención & control , Neoplasias Renales/secundario , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/prevención & control , Neoplasias del Bazo/prevención & control , Neoplasias del Bazo/secundario , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ceramides, serve as central mediators in sphingolipid metabolism and signaling pathways. They function in signaling events which induce apoptosis, cell cycle arrest, and autophagic responses. In cancer cells, ceramide levels are often suppressed by the up-regulation of ceramide-metabolizing enzymes or the down-regulation of ceramide-generating enzymes, resulting in increased cancer cell survival. Chemotherapeutic drugs and radiation therapy have been shown to increase intracellular ceramide levels leading to anti-cancer effects. Anti-cancer effects have also been seen in cancer cells with the use of exogenous short-chain ceramides. Our laboratory has synthesized a library of ceramide analogs and tested their effects on breast cancer cell lines. Analog 315 has been shown to be the most effective ceramide analog in our library. Here, we are reporting a large-scale synthesis of that analog is reported.