Anastasia Papachristodoulou^{1, 2}, Magafoula Tsoukala^{1, 2}, Dimitra Benaki², Sarantos Kostidis², Katerina Gioti¹, Nektarios Aligiannis³, Harris Pratsinis⁴, Dimitris Kletsas⁴, Alexios-Leandros Skaltsounis³, Emmanuel Mikros^2,, Roxane Tenta^1,

The phenolic component Oleuropein (OLEU), a bioactive natural product, has recently shown antiproliferative properties. Doxorubicin (DXR) is an anthracycline present in many chemotherapeutic schemes, although limited due to its cardio-toxic effects. Important research effort has been devoted therefore, to reducing DXR toxicity without compromising its antitumor efficacy. The anticancer actions of DXR and OLEU were assessed, on PC-3 prostate cancer cells, while cell cycle distribution and rate of apoptosis were assessed by flow cytometry. The autophagic process was determined via immunoblotting and immunofluorescent staining. Finally, cell extracts were analyzed by NMR spectroscopy. The present study showed that both DXR and OLEU inhibited PC-3 cells proliferation, while the co-treatment with DXR and OLEU resulted in an additive inhibition. Although the addition of OLEU to DXR did not alter significantly the cell cycle distribution, exhibited by each treatment alone, and produced a marginal increase on the rate of apoptosis, both compounds produced a remarkable induction of autophagy. In addition, treated cells exhibited significant metabolite alterations. This study demonstrates that OLEU, a basic component of the everyday diet, is capable of lowering significantly the cytotoxic dose of DXR, while obtaining an important anti-proliferative effect in prostate cancer cells.

oleuropein, doxorubicin, autophagy, prostate, metabolic profiling