Grape seed extracts modify the outcome of oxaliplatin in colon cancer cells by interfering with cellular mechanisms of drug cytotoxicity

// Letizia Porcelli 1 , Rosa Maria Iacobazzi 1 , Anna Elisa Quatrale 1 , Carlo Bergamini 2 , Nunzio Denora 3 , Pasquale Crupi 2 , Donato Antonacci 2 , Anita Mangia 4 , Giovanni Simone 5 , Nicola Silvestris 6 and Amalia Azzariti 1 1 Experimental Pharmacology Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy 2 CRA-UTV Research Unit for Viticulture and Enology in Southern Italy, Turi, Italy 3 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Bari, Italy 4 Biomorphology Laboratory, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy 5 Pathological Anatomy, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy 6 Medical Oncology, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy Correspondence to: Amalia Azzariti, email: a.azzariti@oncologico.bari.it Keywords: grape seed extracts, colon cancer cells, oxaliplatin, apoptosis, transport systems Received: November 22, 2016     Accepted: January 17, 2017     Published: February 07, 2017 ABSTRACT Grape seed extracts are commonly utilized as dietary supplements for their antioxidant properties, even from cancer patients. However, whether these natural extracts interfere with chemotherapeutics utilized in colon cancer treatment is still poorly investigated. The cytotoxicity of extracts from Italia and Palieri cultivars either alone or in combination with oxaliplatin was evaluated in colon cancer cells. Grape seed extracts displayed anti-proliferative activity depending on the concentration utilized through apoptosis induction. In combination, they affected the activation of Erk1/2 and counteracted the intrinsic and the extrinsic pathway of apoptosis, the DNA damage and the generation of ROS induced by oxaliplatin. Noteworthy grape seed extracts strongly enhanced the uptake of oxaliplatin into all cells, by affecting the cell transport system of platinum. The addition of these natural extracts to oxaliplatin strongly reduced the cellular response to oxaliplatin and allowed a huge accumulation of platinum into cells. Here, we shed light on the chemical biology underlying the combination of grape seed extracts and oxaliplatin, demonstrating that they might be detrimental to oxaliplatin effectiveness in colon cancer therapy.