RESUMEN
We sought to determine whether seliciclib (CYC202, R-roscovitine) could increase the antitumor effects of doxorubicin, with no increase in toxicity, in an MCF7 breast cancer xenograft model. The efficacy of seliciclib combined with doxorubicin was compared with single agent doxorubicin or seliciclib administered to MCF7 cells and to nude mice bearing established MCF7 xenografts. Post-treatment cells and tumors were examined by cell cycle analysis, immunohistochemistry and real-time PCR. Seliciclib significantly enhanced the antitumor effect of doxorubicin without additional murine toxicity. MIB1 (ki67) immunohistochemistry demonstrated reduced proliferation with treatment. The levels of p21 and p27 increased after treatment with doxorubicin or seliciclib alone or in combination, compared to untreated controls. However, no changes in p53 protein (DO1, CM1), survivin or p53 phosphorylation (SER15) were observed in treated tumors compared with controls. In conclusion, the CDK inhibitor seliciclib (R-roscovitine) enhances the antitumor effect of doxorubicin in MCF7 tumors without increased toxicity with a mechanism that involves cell cycle arrest rather than apoptosis.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Quinasas Ciclina-Dependientes/metabolismo , Doxorrubicina/administración & dosificación , Neoplasias Mamarias Animales/tratamiento farmacológico , Purinas/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Inhibidores de Proteínas Quinasas/administración & dosificación , RoscovitinaRESUMEN
The majority of human tumors bear inactive p53 or cellular factors that down-regulate the expression and activity of the p53 network. Therefore, finding therapies that are effective in such tumors is of great interest. Usnic acid, a normal component of lichens, showed activity against the wild-type p53 breast cancer cell line MCF7 as well as the non-functional p53 breast cancer cell line MDA-MB-231 and the lung cancer cell line H1299 (null for p53). In MCF7 cells treated with usnic acid, although there was an accumulation of p53 and p21 proteins, the transcriptional activity of p53 remained unaffected. We also found that there was no phosphorylation of p53 at Ser15 after treatment of MCF7 cells with usnic acid, suggesting that the oxidative stress and disruption of the normal metabolic processes of cells triggered by usnic acid does not involve DNA damage. The property of usnic acid as a non-genotoxic anti-cancer agent that works in a p53-independent manner makes it a potential candidate for novel cancer therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzofuranos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Daño del ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Estrés Oxidativo , Fosforilación , Transcripción Genética/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
The efficacy of MDI-301, a non-toxic novel synthetic retinoid, was found to be equivalent to the natural 9-cis-retinoic acid (RA) in vitro against estrogen-dependent MCF7 and T47D breast cancer cell lines which express RA receptor (RAR) alpha. Both retinoids also showed similar efficacy against established PC-3 prostate carcinoma xenografts. MCF7 tumor xenografts showed a reduction in tumor growth of 48% without systemic side-effects upon treatment with MDI-301 compared with MCF7 controls. Tumor xenografts derived from MDA-MB-231, an estrogen-independent breast cancer cell line that expresses low levels of RARalpha, were unresponsive. This study demonstrates that MDI-301 is as efficacious as 9-cis-RA against cancer cells with RARalpha, with no signs of toxicity in vivo, making it a potential candidate for cancer therapy.
