Abstract
Resveratrol (RV, 3,4ʹ,5-trihydroxystilbene) is naturally produced by a wide variety of plants including grapes and peanuts (Arachis hypogaea). However, the yield of RV from peanut stem and its potential radiosensitizing effects in prostate cancer (PCa) have not been well investigated. In this study, we characterized RV in peanut stem extract (PSE) for the first time and showed that both RV and PSE dose-dependently induced cell death in DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells with the radioresistant phenotype. Furthermore, the combination of radiation with either RV or PSE induced the death of radioresistant PCa cells through delayed repair of radiation-induced DNA double-strand break (DSB) and prolonged G2/M arrest, which induced apoptosis. The administration of RV and PSE effectively enhanced radiation therapy in the shDAB2IP PCa xenograft mouse model. These results demonstrate the promising synergistic effect of RV and PSE combined with radiation in the treatment of radioresistant PCa.
Highlights
Because the peanut stem extract (PSE) contained a high RV content, we first examined whether PSE inhibited the growth of human prostate cancer (PCa) cells
Our data showed that the co-localization of γ-H2AX and 53BP1 foci significantly increased in the cells co-treated with ionizing radiation (IR) and PSE compared to that in cells treated with IR alone (S2B Fig). These results demonstrate that PSE effectively enhanced the IR-induced double-strand break (DSB) and prolonged the DSB repair kinetics of the PCa cells
We showed that the radioresistance of shDAB2IP PCa cells was overcome by co-treatment with IR and either RV or PSE (Fig 3)
Summary
Antibody specific for 53BP1 and β-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Antibodies against cleaved PARP (Asp214), cleaved Caspase (Asp175) and Caspase 9 were purchased from Proteintech (Chicago, IL). Antibodies against phospho-ATM, ATM, phospho-checkpoint kinase 2 (CHK2), CHK2, phospho-p53, and p53were purchased from Cell Signaling (Danvers, MA). Anti-phospho-γ-H2AX (Ser139) antibody was purchased from Millipore (Billerica, MA). Alexa Fluor 488–conjugated goat anti-mouse IgG, and Alexa Fluor 594–conjugated goat anti-rabbit IgG, and 4’,6-diamidino-2-phenylindole (DAPI) were purchased from Molecular Probes (Invitrogen, Carlsbad, CA). All other reagents were purchased from Sigma-Aldrich (St. Louis, MO)
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