%0 Journal Article
%T DTNQ-Pro, a Mimetic Dipeptide, Sensitizes Human Colon Cancer Cells to 5-Fluorouracil Treatment
%A Isabel Gomez-Monterrey
%A Pietro Campiglia
%A Ilaria Scognamiglio
%A Daniela Vanacore
%A Alessandra Dicitore
%A Angela Lombardi
%A Michele Caraglia
%A Ettore Novellino
%A Paola Stiuso
%J Journal of Amino Acids
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/509056
%X The resistance of growing human colon cancer cells to chemotherapy agents has been correlated to endogenous overexpression of stress proteins including the family of heat shock proteins (HSPs). Previously, we have demonstrated that a quinone-based mimetic dipeptide, named DTNQ-Pro, induced differentiation of growing Caco-2 cells through inhibition of HSP70 and HSP90. In addition, our product induced a HSP27 and vimentin intracellular redistribution. In the present study, we have evaluated whether a decrease of stress proteins induced by DTNQ-Pro in Caco-2 cells could sensitize these cells to treatment with 5-fluorouracil (5-FU) cytotoxicity. The pretreatment of Caco-2 with 500£¿nM of DTNQ-Pro increases lipid peroxidation and decreases expression of p38 mitogen-activated protein kinase (MAPK) and FOXO3a. At the same experimental conditions, an increase of the 5-FU-induced growth inhibition of Caco-2 cells was recorded. These effects could be due to enhanced DTNQ-Pro-induced membrane lipid peroxidation that, in turn, causes the sensitization of cancer cells to the cytotoxicity mediated by 5-FU. 1. Introduction Adenocarcinoma cells, such as colorectal cancer (CRC) cells, are remarkably resistant to radiation or chemotherapy-induced damage. As a consequence, the tumours are hard to treat and often proliferate rapidly, even under conditions that may adversely affect normal cells. For several years, 5-fluorouracil (5-FU), a pyrimidine antimetabolite, has been the drug of choice for the treatment of CRC as well as head and neck, pancreatic, and breast carcinomas. 5-FU is known to block DNA synthesis by the inhibition of thymidylate synthase (TS), which is regulated by cell cycle proteins controlled by phosphorylation [1]. Unfortunately, many of the schedules based upon 5-FU alone or in combination with other agents become ineffective during the course of the treatment due to the occurrence of drug resistance to 5-FU. Between several survival pathways activated in cancer cells to antagonize the antiproliferative activities of antineoplastic agents [2¨C4]. The mechanisms underlying the survival advantage can also be partially related to the increased expression of stress proteins [5, 6]. In fact, in contrast to normal cells, the basal levels of inducible heat shock proteins (HSPs) are frequently higher in tumour cells [7, 8]. The high expression of members of the HSP family in CRC cells has been associated with both metastases and resistance to chemotherapy. Moreover, in experimental models, HSP27 and HSP70 have been shown to increase tumorigenicity of cancer
%U http://www.hindawi.com/journals/jaa/2013/509056/