title: Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness-related pathways in colorectal cancer cells.
abstract: Despite the demonstrated benefits of anti-EGFR/VEGF targeted therapies in metastatic colorectal cancer (mCRC), many patients initially respond, but then show evidence of disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/VEGF and cyclooxygenase-2 (COX-2) may aid the treatment and management of mCRC patients. The dual tyrosine kinase inhibitor AEE788 and celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in colorectal cancer cells. COX-2 inhibition with celecoxib augmented the antitumoral and antiangiogenic efficacy of AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down-regulation of VEGF production by cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined AEE788/celecoxib treatment prevented β-catenin nuclear accumulation in tumor cells. This effect was associated with a significant downregulation of FOXM1 protein levels and an impairment in the interaction of this transcription factor with β-catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of AEE788 and celecoxib not only demonstrated enhanced anti-tumoral efficacy in colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness-related pathways. Therefore, the simultaneous targeting of EGFR/VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing therapies in colorectal cancer.
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: Valverde
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Peñarando
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Amanda
authors.initials: A
authors.lastname: Cañas
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: López-Sánchez
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Conde
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hernández
authors.affiliation: Research Unit, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Peralbo
authors.affiliation: Research Unit, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain.
authors.forename: Chary
authors.initials: C
authors.lastname: López-Pedrera
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: de la Haba-Rodríguez
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Aranda
authors.affiliation: Oncology Department, Maimonides Institute of Biomedical Research (IMIBIC), Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rodríguez-Ariza
mesh_terms: D017209:Apoptosis; D018938:Caco-2 Cells; D000068579:Celecoxib / Q000008:administration & dosage; D002453:Cell Cycle; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry*; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009389:Neovascularization, Pathologic; D011687:Purines / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011687:Purines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C512478:EGFR protein, human; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788; D000068579:Celecoxib