PDGFR and IGF-1R Inhibitors Induce a G2/M Arrest and Subsequent Cell Death in Human Glioblastoma Cell Lines
Por:
Carrasco-Garcia E, Martinez-Lacaci I, Mayor-López L, Tristante E, Carballo-Santana M, García-Morales P, Ventero M, Fuentes M, Rodriguez-Lescure Á and Saceda M
Publicada:
1 sep 2018
Resumen:
Glioblastomas are highly resistant to radiation and chemotherapy. Currently, there are no effective therapies for this type of tumor. Signaling mechanisms initiated by PDGFR and IGF-1R are important in glioblastoma, and inhibition of the signal transduction pathways initiated by these receptors could be a useful alternative strategy for glioblastoma treatment. We have studied the effects of the PDGFR inhibitor JNJ-10198409 (JNJ) and the IGF-1R inhibitor picropodophyllin (PPP) in glioblastoma cell lines as well as in primary cultures derived from patients affected by this type of tumor. JNJ and PPP treatment blocked PDGFR and IGF-1R signaling respectively and reduced Akt and Erk 1/2 phosphorylation. Both inhibitors diminished cell proliferation, inducing a G2/M block of the cell cycle. Cell death induced by JNJ was caspase-dependent, Annexin-V positive and caused PARP cleavage, especially in T98 cells, suggesting an apoptotic mechanism. However, cell death induced by PPP was not completely inhibited by caspase inhibitors in all cell lines apart from LN-229 cells, indicating a caspase-independent mechanism. Several inhibitors targeted against different cell death pathways could not block this caspase-independent component, which may be a non-programmed necrotic mechanism. Apoptotic arrays performed in T98 and LN-229 cells upon JNJ and PPP treatment revealed that procaspase 3 levels were augmented by both drugs in T98 cells and only by JNJ in LN229-cells. Furthermore, XIAP and survivin levels were much higher in LN-229 cells than in T98 cells, revealing that LN-229 cells are more susceptible to undergo caspase-independent cell death mechanisms. JNJ and PPP combination was more effective than each treatment alone.
Filiaciones:
:
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Alicante, Spain.
División de Neurooncología, Instituto Biodonostia, 20014 San Sebastián (Guipuzkoa), Spain.
Martinez-Lacaci I:
Unidad AECC de Investigación Traslacional en Cáncer, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.
Ventero M:
Unidad de Investigación ISABIAL-FISABIO, Hospital General Universitario de Alicante, 03010 Alicante, Spain.
:
Servicio de Oncología del Hospital General Universitario de Elche, 03203 Alicante, Spain.
:
Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, 03203 Alicante, Spain.
gold, Green Submitted, Green Published
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