BACKGROUND: Glioblastoma (GBM) is the most common and fatal human brain tumor, with the worst prognosis. The aberrant microenvironment, enhanced by the activation of proangiogenic mediators such as hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and their downstream effectors, sustain GBM malignancy. Proangiogenic signaling represents an attractive chemotherapeutic target. Recent evidence suggests a therapeutic benefit from aspirin (acetylsalicylic acid, or ASA) intake in reducing risk and cancer progression. METHODS: In the present study, human primary GBM- endothelial cells (ECs) were used to ascertain whether ASA could inhibit angiogenesis and improve cell sensitivity to drugs. The impact of ASA was observed by measuring cell viability, tube-like structure formation, migration, VEGF production, and proliferative, proangiogenic, and apoptotic modulators expression, such as HIF-1 alpha/VEGF/vascular endothelial growth factor receptor/(VEGFR)-1/VEGFR-2, Ras/ mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/AKT signaling axis, and Bcl-2-associated X protein/B-cell lymphoma 2 (BCL-2) ratio. Furthermore, we evaluated the effect of ASA alone or in combination with temozolomide (TMZ), bevacizumab (BEV), and sunitinib (SUN). RESULTS: Our data reported that ASA affected GBM-EC viability, tube-like structure formation, cell migration, and VEGF releasing in a dose-dependent manner and that combined treatments with TMZ, BEV, and SUN synergized to counteract proangiogenic cell ability. mRNA expression analysis displayed a marked effect of ASA in reducing VEGF, VEGFR-1, HIF-1 alpha, RAS, mitogen-activated protein kinase kinase, AICT, and BCL-2, as well a combined anticancer effect of ASA together with TMZ, BEV, and SUN. Levels of HIF-1 alpha, VEGFR-2, Bcl-2-associated X protein, and BCL-2 protein expression confirmed a positive trend. CONCLUSIONS: ASA and antiangiogenic therapies showed synergetic anticancer efficacy in human primary GBM-ECs. Thus, the combination of conventional chemotherapy with ASA may offer a new strategy to counteract tumor malignancy.
Aspirin Affects Tumor Angiogenesis and Sensitizes Human Glioblastoma Endothelial Cells to Temozolomide, Bevacizumab, and Sunitinib, Impairing Vascular Endothelial Growth Factor-Related Signaling / S. Navone, L. Guarnaccia, C. Cordiglieri, F.M. Crisa', M. Caroli, M. Locatelli, L. Schisano, P. Rampini, M. Miozzo, N. La Verde, L. Riboni, R. Campanella, G. Marfia. - In: WORLD NEUROSURGERY. - ISSN 1878-8750. - 120(2018 Dec), pp. E380-E391.
|Titolo:||Aspirin Affects Tumor Angiogenesis and Sensitizes Human Glioblastoma Endothelial Cells to Temozolomide, Bevacizumab, and Sunitinib, Impairing Vascular Endothelial Growth Factor-Related Signaling|
GUARNACCIA, LAURA (Co-primo)
CAMPANELLA, ROLANDO (Penultimo)
|Parole Chiave:||Angiogenesis; Aspirin; Endothelial cells; Glioblastoma; HIF-1 alpha; VEGF|
|Settore Scientifico Disciplinare:||Settore MED/27 - Neurochirurgia|
Settore BIO/10 - Biochimica
|Data di pubblicazione:||dic-2018|
|Data ahead of print / Data di stampa:||ago-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.wneu.2018.08.080|
|Appare nelle tipologie:||01 - Articolo su periodico|