Corrales, L. (Leticia)
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- Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo(Biomed Central, 2010-06) Pio, R. (Rubén); Lopez-Picazo, J.M. (José M.); Corrales, L. (Leticia); Hsu, Y.F. (Y. F.); Gurpide, A. (Alfonso); Montuenga-Badia, L.M. (Luis M.); Ajona, D. (Daniel)Background Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug. Results EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated. Conclusions We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
- Nanoparticules muco-pénétrantes: véhicules pour l’administration orale du paclitaxel(Académie Nationale de Pharmacie, 2013) Pio, R. (Rubén); Agüeros, M. (Maite); Zabaleta, V. (Virginia); Corrales, L. (Leticia); Espuelas, S. (Socorro); Calleja, P. (Patricia); Irache, J.M. (Juan Manuel)Paclitaxel is an anticancer drug used as solution for perfusion for the treatment of certain types of cancers. In the last years, a number of strategies have been proposed for the development of an oral formulation of this drug. However, this task is quite complicated due to the poor aqueous solubility of paclitaxel as well as the fact that this compound is substrate of the intestinal P-glycoprotein and the cytochrome P450 enzymatic complex. In this work, we have developed pegylated nanoparticles with mucopenetrating properties in order to conduct paclitaxel onto the surface of the enterocyte. These nanoparticles displayed a size of about 180 nm and a drug loading close to 15% by weight. The pharmacokinetic study in mice has shown that these nanoparticles were capable to offer therapeutic plasma levels of paclitaxel up to 72 hours. In addition, the oral relative bioavailability of paclitaxel when loaded in nanoparticles pegylated with poly(ethylene glycol) 2000 (PEG) was found to be 85%. In a subcutaneous model of tumour in mice, these pegylated nanoparticles administered orally every 3 days have demonstrated a similar efficacy than Taxol® administered intravenously every day during 9 days. All of these results suggested that these pegylated nanoparticles were capable to cross the mucus layer of the gut and, then, reach the surface of the enterocytes. The PEG molecules would facilitate the adhesion of nanoparticles to this epithelial surface, minimise the pre-systemic metabolism of paclitaxel and, thus, promote its absorption.
- Complement factor H is elevated in bronchoalveolar lavage fluid and sputum from patients with lung cancer(American Association for Cancer Research, 2010-08-27) Seijo, L. (Luis); Pajares, M.J. (María José); Garcia, J. (Javier); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Schmidt, B. (Bernd); Fleischhacker, M. (M.); Nadal, E. (Ernest); Corrales, L. (Leticia); Montuenga-Badia, L.M. (Luis M.); Witt, C. (Christian); Ajona, D. (Daniel); Cardenal, F. (F.); Zulueta, J. (Javier)Abstract Background: Cytologic examination of specimens obtained from the respiratory tract is a lung cancer diagnostic procedure with high specificity, but moderate sensitivity. The use of molecular biomarkers may enhance the sensitivity of cytologic examination in the detection of lung cancer. Methods: Complement factor H, a protein secreted by lung cancer cells, was quantified in a series of bronchoalveolar lavage supernatants from lung cancer patients and patients with nonmalignant respiratory diseases. Albumin, total protein content, and hemoglobin were also analyzed. Results were validated in independent sets of bronchoalveolar lavage and sputum supernatants. Results: There was a significantly higher concentration of factor H in bronchoalveolar lavage samples from lung cancer patients. The sensitivity and specificity of the factor H test was 82% and 77%, respectively. These results were validated in an independent set of patients with nearly identical results. Furthermore, 70% and 45% of bronchoalveolar lavage fluids from central and peripheral tumors, respectively, reported as cytologically negative were classified as positive using this marker. Finally, the test was evaluated in a series of sputum supernatants from lung cancer patients and controls. The sensitivity and specificity of the factor H test in this series was 80% and 88%, respectively. Conclusion: Factor H is elevated in bronchoalveolar lavage and sputum from lung cancer patients. Impact: Measurement of molecular biomarkers, such as complement factor H, may be used in the future as an adjunct to cytology in the diagnosis of malignant pulmonary diseases.
- Pharmacokinetics and antitumor efficacy of paclitaxel-cyclodextrin complexes loaded in mucus-penetrating nanoparticles for oral administration(Future Medicine, 2014) Pio, R. (Rubén); Corrales, L. (Leticia); Espuelas, S. (Socorro); Calleja, P. (Patricia); Irache, J.M. (Juan Manuel)The authors report a novel approach for enhancing the oral absorption of paclitaxel (PTX) by encapsulation in poly(anhydride) nanoparticles (NPs) containing cyclodextrins and poly(ethylene glycol). Materials & methods: Formulations were prepared using the solvent displacement method. Subsequently, pharmacokinetics and organ distribution assays were evaluated after oral administration into C57BL/6J mice. In addition, antitumor efficacy studies were performed in a subcutaneous tumor model of Lewis lung carcinoma. Results: PTX-loaded NPs displayed sizes between 190–300 nm. Oral NPs achieved drug plasma levels for at least 24 h, with an oral bioavailability of 55–80%. Organ distribution studies revealed that PTX, orally administered in NPs, underwent a similar distribution to intravenous Taxol® (Bristol-Myers-Squibb, NJ, USA). For in vivo antitumor assays, oral strategy maintained a slower tumor growth than intravenous Taxol. Conclusion: PTX orally administered in poly(anhydride) NPs, combined with cyclodextrins and poly(ethylene glycol), displayed sustained plasma levels and significant antitumor effect in a syngenic tumor model of carcinoma in mice.
- Repetitive nicotine exposure leads to a more malignant and metastasis-prone phenotype of SCLC: a molecular insight into the importance of quitting smoking during treatment(Oxford University Press, 2010) Rouzaut, A. (Ana); Corrales, L. (Leticia); Gonzalez-Moreno, O. (Óscar); Martinez-Garcia, E. (Eva); Salvo, E. (Elizabeth); Teijeira, A. (Álvaro); Irigoyen, M. (Marta)Cigarette smoking is strongly correlated with the onset of lung cancer. Nicotine, a major component in cigarette smoke, has been found to promote tumor growth and angiogenesis, as well as protect cancer cells from apoptosis. Among all lung cancer cases, small cell lung cancer (SCLC) is found almost exclusively in smokers; metastasis and chemoresistance are the main reasons for the high mortality rates associated with SCLC. Retrospective studies have shown that patients with tobacco-related cancers who continue to smoke after their diagnosis display lower response rates and a shorter median survival compared with those who stop smoking. In the current work, we examined the effects of acute and repetitive exposure to nicotine, in the concentrations found in the lungs of active smokers, on the malignant properties of N417 SCLC cells in vitro. We observed that repetitive nicotine exposure induced a neuronal-like appearance in N417 cells along with increased adhesion to the extracellular matrix and chemoresistance. These changes were accompanied by enhanced migration through collagen matrices and adhesion to and transmigration across lymphatic endothelial cell monolayers. SCLC differentiation reverted after cessation of nicotine exposure. Here, we provide evidence for the leading role of the CXCR4/CXCL12 axis in these phenomena. Finally, we show how nicotine-differentiated N417 cells produced bigger and more vascularized tumors in mice, with lower apoptotic rates, than their nondifferentiated counterparts. In short, these findings identify the mechanisms through which nicotine increases SCLC malignancy and provide further evidence that CXCR4 is a potential anticancer target for nicotine-associated SCLC.
- Complement activation in non-small cell lung cáncer and its effect on tumor progresión(Servicio de Publicaciones de la Universidad de Navarra, 2012) Corrales, L. (Leticia); Pio, R. (Rubén)HYPOTHESIS The hypothesis of the present work is that tumor cells express on their surface tumorassociated antigens that have the potential to activate the complement system. At the same time, tumor cells have developed mechanisms that make them resistant to complement cytotoxic effects. The subsequent effects of complement activation on complement-resistant cancer cells play a pivotal role in the development of malignant features, ending in tumor progression. OBJECTIVES 1. To study complement activation by the alternative and classical pathways on non-small cell lung cancer (NSCLC) cells and normal bronchial epithelial cells. 2. To study the expression, at the mRNA and protein levels, of the main complement inhibitory proteins in NSCLC and normal bronchial epithelial cells. 3. To study the role of complement in a syngeneic mouse model of lung cancer, with special interest in tumor-associated characteristics of the microenvironment such as angiogenesis and immunosuppression. 4. To evaluate the tumor-promoting effects of complement on NSCLC cells.