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

Letizia Porcelli,Amalia Azzariti,Donato Antonacci,Anna Elisa Quatrale,Nicola Silvestris,Nunzio Denora,Giovanni Simone,Pasquale Crupi,Rosa Maria Iacobazzi,Carlo Bergamini,Anita Mangia

doi:10.18632/oncotarget.15139

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.

Highlights

Advances in chemotherapy have contributed to the increased survival rates of cancer patients
We investigated if grape seed extract (GSE), from Italia e Palieri cultivars, reduced the proliferation of colon cancer cell lines and if they affected the response to oxaliplatin, by assessing the mechanisms underlying GSEs-oxaliplatin interaction in such tumors which might impact on the outcome of the oxaliplatin-based chemotherapy
Both GSEs at 100 μg/ml [29] induced a dose-dependent reduction of cell viability, when GSEs were combined to oxaliplatin, they reduced the oxaliplatindependent inhibition of cell proliferation in HT-29 and Lovo cells while they did not affect the drug cytotoxicity in Colo205 and HCT116

Summary

Introduction

Advances in chemotherapy have contributed to the increased survival rates of cancer patients. The clinical efficacy of chemotherapy is often limited by its non-cancer specific effects causing damage to proliferating normal cells, especially those of the bone marrow and of the gastrointestinal tract. Besides these primary side effects, there are a number of other toxicities that the patient has to bear during chemotherapy such as fatigue, nausea, vomiting, diarrhea, etc. These are often approached by administering to patients supplements to improve their general status [1, 2]. Bioactive phytochemicals, those already present in the diet, offer promising options for the development of more effective strategies for the prevention or treatment www.impactjournals.com/oncotarget of cancers and they are often utilized as complementary or alternative medicine [3,4,5,6,7,8]

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