PDGFR and IGF-1R Inhibitors Induce a G2/M Arrest and Subsequent Cell Death in Human Glioblastoma Cell Lines

Abstract

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.

CLytA-DAAO, Free and Immobilized in Magnetic Nanoparticles, Induces Cell Death in Human Cancer Cells

“…Both, free and immobilized, CLytA-DAAO chimera are able to induce cell death by increasing ROS production, which caused DNA damage in several colon carcinoma and pancreatic adenocarcinoma cell lines as well as in glioblastoma cell lines derived from primary cultures obtained in our laboratory directly from glioblastoma patients, at doses that are safe for non-tumor cells. Interestingly, the cell death evoked by the enzyme could be executed by apoptotic or necrotic mechanisms depending on the tumor origin.The reasons to select these types of tumors in our study were their frequency, mortality, and resistance to other treatments and also our laboratory experience, since we have been working in these models for many years [19][20][21][22][23]. This localized therapy reduces the dose of drug needed, improving the effectiveness and decreasing adverse effects.…”

“…The reasons to select these types of tumors in our study were their frequency, mortality, and resistance to other treatments and also our laboratory experience, since we have been working in these models for many years [19][20][21][22][23]. This localized therapy reduces the dose of drug needed, improving the effectiveness and decreasing adverse effects.…”

Glioma Cells With Genetically Engineered IGF-I Receptor Downregulation Can Persist in the Brain in a Dormant State

“…The critical role that the IGF axis plays in the growth of GBM has been well documented in various experimental models ( 6 , 22 , 23 ). In early studies, the IGFs were shown to enhance 3D growth of glioblastoma ( 21 ) and more recently, high IGF-IR expression levels were identified as an independent prognostic factor associated with shorter survival, a poorer response to temozolomide ( 4 ) and resistance to anti-EGFR ( 24 ) and anti-PDGFR ( 25 ) treatments in GBM patients.…”

“…In many human malignancies, including GBM, upregulated expression of IGF-IR, IGF-I, IGF-II or combinations thereof have been documented (2,4). Therefore, targeting the IGF system, by inhibiting ligand or receptor synthesis and/or function could provide effective therapeutic approaches to the treatment of GBM (5)(6)(7)(8)(9).…”

A thirteen‑gene set efficiently predicts the prognosis of glioblastoma

“…Furthermore, ZNF24 may contribute to cell cycle promotion and maintenance of the progenitor stage of neural cells (41). Platelet-derived growth factor receptor (PDGFR) signaling is a crucial mechanism for the initiation and development of GBM (42). In GBM cell lines, ZNF24 negatively regulates two transcription factors, vascular endothelial growth factor (VEGF) and PDGFR-β (43).…”