Effect of citrus peel extracts on the cellular quiescence of prostate cancer cells

The re-entry of quiescent cancer cells to the cell cycle plays a key role in cancer recurrence, which can have a high risk after primary treatment. Citrus peel extracts (CPEs) contain compounds that can impair tumour growth, however the mechanism of action and effects on cell cycle regulation remain unclear. In this study, the capacity of ethyl acetate: hexane extract (CPE/hexane) and water extract (CPE/water) to modulate cell cycle re-entry of quiescent (PC-3 and LNCaP) prostate cancer cells was tested in an in vitro culture system. Cell cycle analysis showed that the quiescent PC-3 and LNCaP cancer cells in the presence of CPE/water were impaired in their ability to enter S phase where only 2-3% reduction of G0/G1 cells was noted compared to 12-18% reduction for control cells. In contrast, the CPE/hexane did not show any cell cycle inhibition activity in both cell lines. A low DNA synthesis rate and weak apoptosis were observed in quiescent cancer cells treated with CPEs. Hesperidin and narirutin, the predominant flavonoids found in citrus, were not responsible for the observed biological activity, implicating alternative bioactive compounds. Notably, citric acid was identified as one of the compounds present in CPE that acts as a cell cycle re-entry inhibitor. Citric acid exhibited a higher cell toxicity effect on PC-3 prostate cancer cells than non-cancerous RWPE-1 prostate cells, suggesting specific benefits for cancer treatment. In conclusion, CPE containing citric acid together with various bioactive compounds could be used as a chemopreventive agent for post-therapy cancer patients.