BACKGROUND: Prostate cancer (PrCa) displays resistance to radiotherapy (RT) and 
requires radiotherapy dose escalation which is associated with greater toxicity. 
This highlights a need to develop radiation sensitizers to improve the efficacy 
of RT in PrCa. Ionizing radiation (IR) stimulates pathways of IR-resistance and 
survival mediated by the protein kinase Akt but it also activates the metabolic 
energy sensor and tumor suppressor AMP-Activated Protein Kinase (AMPK). Here, we 
examined the effects of the polyphenol resveratrol (RSV) on the IR-induced 
inhibition of cell survival, modulation of cell cycle and molecular responses in 
PrCa cells.
METHODS: Androgen-insensitive (PC3), sensitive (22RV1) PrCa and PNT1A normal 
prostate epithelial cells were treated with RSV alone (2.5-10 μM) or in 
combination with IR (2-8 Gy). Clonogenic assays, cell cycle analysis, microscopy 
and immunoblotting were performed to assess survival, cell cycle progression and 
molecular responses.
RESULTS: RSV (2.5-5 μM) inhibited clonogenic survival of PC3 and 22RV1 cells but 
not of normal prostate PNT1A cells. RSV specifically sensitized PrCa cells to 
IR, induced cell cycle arrest at G1-S phase and enhanced IR-induced nuclear 
aberrations and apoptosis. RSV enhanced IR-induced expression of DNA damage 
(γH2Ax) and apoptosis (cleaved-caspase 3) markers as well as of the cell cycle 
regulators p53, p21(cip1) and p27(kip1). RSV enhanced IR-activation of ATM and 
AMPK but inhibited basal and IR-induced phosphorylation of Akt.
CONCLUSIONS: Our results suggest that RSV arrests cell cycle, promotes apoptosis 
and sensitizes PrCa cells to IR likely through a desirable dual action to 
activate the ATM-AMPK-p53-p21(cip1)/p27(kip1) and inhibit the Akt signalling 
pathways.