RESUMEN
Use of drug combinations that target different pathways involved in the development and progression of prostate cancer (PCa) has emerged as an alternative to overcome the resistance caused by drug monotherapies. The antiandrogen abiraterone acetate and the PI3K/Akt inhibitor NVP-BEZ235 (BEZ235) may be suitable options for the prevention of drug resistance and the inhibition of PCa progression. The aim of the present study was to evaluate whether abiraterone acetate and BEZ235 achieve superior therapeutic effects to either drug administered as monotherapy, in the early stages of PCa in an androgen-dependent system. Our study showed that each drug might impair tumor growth by reducing proliferation and increasing cell death when administered as monotherapy. However, tumor growth continued to progress with each drug monotherapy and some important side effects were related to BEZ. Conversely, when used in combination, the drugs impaired the inflammatory response, decreased hyperplastic lesions, and blocked tumor progression from premalignant to a malignant stage. Our data showed that the strategy to block the androgenic and PI3K/AKT/mTOR pathway is an effective therapeutic option and should be investigated including distinct PI3K pathway inhibitors.
Asunto(s)
Acetato de Abiraterona/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Imidazoles/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Andrógenos/metabolismo , Animales , Carcinogénesis , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Masculino , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ratas , Ratas Endogámicas F344 , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Bisphenol A (BPA) is one hormonally active chemical with potential deleterious effects on reproductive organs, including breast and prostate. In contrast, genistein (GEN) is the major phytoestrogen of soy that presents potential protective effects against hormone-dependent cancers, including that of the prostate. Thus, pregnant Sprague-Dawley rats were treated with BPA at 25 or 250 µg/kg/day by gavage from gestational day (GD) 10-21 with or without dietary GEN at 250 mg/kg/chow (â¼5.5 mg/kg/day). Then, male offspring from different litters were euthanized on post-natal day (PND) 21 and 180. At PND21, BPA 25 exposure induced early prostatic changes while dietary GEN attenuated some deleterious actions this xenoestrogen on epithelial cell proliferation levels, androgen receptor expression and prostatic architecture in male offspring. At PND180, a significant increase in incidence of prostatic multifocal inflammation/reactive hyperplasia and atypical hyperplasia were observed in male offspring from dams that received BPA 25. On the other hand, maternal GEN feeding attenuated some the adverse effects of BPA 25 on prostate disease at late-in-life. This way, the present findings point to preventive action of dietary GEN on deleterious effects of gestational BPA exposure in both early and late prostate development in offspring F1.
Asunto(s)
Suplementos Dietéticos , Estrógenos no Esteroides/antagonistas & inhibidores , Genisteína/uso terapéutico , Fenómenos Fisiologicos Nutricionales Maternos , Fitoestrógenos/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/prevención & control , Próstata/efectos de los fármacos , Animales , Compuestos de Bencidrilo/administración & dosificación , Compuestos de Bencidrilo/antagonistas & inhibidores , Compuestos de Bencidrilo/toxicidad , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estrógenos no Esteroides/administración & dosificación , Estrógenos no Esteroides/toxicidad , Femenino , Masculino , Fenoles/administración & dosificación , Fenoles/antagonistas & inhibidores , Fenoles/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Próstata/metabolismo , Próstata/patología , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Hiperplasia Prostática/prevención & control , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/prevención & control , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo , Organismos Libres de Patógenos Específicos , DesteteRESUMEN
Bisphenol A (BPA) is a chemical that has been investigated for it potential to cause prostate diseases. In this study, pregnant Sprague-Dawley rats were treated with 25 or 250 µg/kg BPA from gestational day (GD) 10 to GD21 with or without concurrent indole-3-carbinol (I3C) feeding. I3C is a phytochemical, and it affords chemoprotection against many types of neoplasia. Male F1 rats from different litters were euthanized on post-natal day (PND) 21 and PND180. BPA-treated groups showed a significant increase in histopathological lesions, but I3C feeding reversed many of these changes, mainly at PND180. Maternal I3C feeding increased prostate epithelial apoptosis in the BPA-treated groups and across age groups. Furthermore, I3C induced partial normalization of the prostate histoarchitecture. The results pointed to a protective effect of maternal I3C feeding during pregnancy in the BPA-exposed male offspring, thereby indicating reduction in the harmful effects of gestational BPA imprinting on the prostate.