PDGFR and IGF-1R Inhibitors Induce a G2/M Arrest and Subsequent Cell Death in Human Glioblastoma Cell Lines
Autor: | Maria Fuentes-Baile, Estefania Carrasco-Garcia, Elena Tristante, P. Garcia-Morales, Álvaro Rodríguez-Lescure, Maria Paz Ventero Martin, Mar Carballo-Santana, Miguel Saceda, Isabel Martínez-Lacaci, Leticia Mayor-López |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway PDFGR Chemistry Cell growth glioblastoma General Medicine Cell cycle Article XIAP 03 medical and health sciences 030104 developmental biology 0302 clinical medicine cell death lcsh:Biology (General) Apoptosis Cell culture 030220 oncology & carcinogenesis Survivin Cancer research Picropodophyllin lcsh:QH301-705.5 IGF-1R |
Zdroj: | Cells r-FISABIO: Repositorio Institucional de Producción Científica Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) Volume 7 Issue 9 Cells, Vol 7, Iss 9, p 131 (2018) r-FISABIO. Repositorio Institucional de Producción Científica instname r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante |
ISSN: | 2073-4409 |
Popis: | 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. |
Databáze: | OpenAIRE |
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