%0 Journal Article
%A Ortiz, Raúl
%A Prados, José
%A Melguizo, Consolación
%A Arias, José L
%A Ruiz, M Adolfina
%A Alvarez, Pablo J
%A Caba, Octavio
%A Luque, Raquel
%A Segura, Ana
%A Aránega, Antonia
%T 5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer
%D 2012
%@ 1176-9114
%U http://hdl.handle.net/10668/569
%X This work aimed to develop a new therapeutic approach to increase the efficacy of 5-fluorouracil (5-FU) in the treatment of advanced or recurrent colon cancer. 5-FU-loaded biodegradable poly(ε-caprolactone) nanoparticles (PCL NPs) were combined with the cytotoxic suicide gene E (combined therapy). The SW480 human cancer cell line was used to assay the combined therapeutic strategy. This cell line was established from a primary adenocarcinoma of the colon and is characterized by an intrinsically high resistance to apoptosis that correlates with its resistance to 5-FU. 5-FU was absorbed into the matrix of the PCL NPs during synthesis using the interfacial polymer disposition method. The antitumor activity of gene E from the phage ϕX174 was tested by generating a stable clone (SW480/12/E). In addition, the localization of E protein and its activity in mitochondria were analyzed. We found that the incorporation of 5-FU into PCL NPs (which show no cytotoxicity alone), significantly improved the drug's anticancer activity, reducing the proliferation rate of colon cancer cells by up to 40-fold when compared with the nonincorporated drug alone. Furthermore, E gene expression sensitized colon cancer cells to the cytotoxic action of the 5-FU-based nanomedicine. Our findings demonstrate that despite the inherent resistance of SW480 to apoptosis, E gene activity is mediated by an apoptotic phenomenon that includes modulation of caspase-9 and caspase-3 expression and intense mitochondrial damage. Finally, a strongly synergistic antiproliferative effect was observed in colon cancer cells when E gene expression was combined with the activity of the 5-FU-loaded PCL NPs, thereby indicating the potential therapeutic value of the combined therapy.
%K colon cancer
%K combined therapy
%K 5-fluorouracil
%K gene therapy
%K E gene
%K poly (ε-caprolactone)
%K Neoplasias del Colon
%K Terapia de Gen
%K Humanos
%K Fluorouracilo
%K Nanopartículas
%K Antineoplásicos
%K Apoptosis
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