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

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 131 ◽  
Author(s):  
Estefania Carrasco-Garcia ◽  
Isabel Martinez-Lacaci ◽  
Leticia Mayor-López ◽  
Elena Tristante ◽  
Mar Carballo-Santana ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Primary Cultures ◽  
Annexin V ◽  
Parp Cleavage ◽  
Glioblastoma Cell ◽  
Cell Death Pathways ◽  
Cell Death Mechanisms ◽  
Glioblastoma Cell Lines ◽  
Apoptotic Mechanism

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.

271 PDGFR and IGF-1R inhibitors induce G2/M arrest and subsequent cell death in human glioblastoma cell lines and primary cultures

2015 ◽  
Vol 51 ◽  
pp. S50
Author(s):  
M. Saceda ◽  
E. Carrasco-Garcia ◽  
L. Mayor-Lopez ◽  
E. Tristante ◽  
M. Carballo-Santana ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Primary Cultures ◽  
Glioblastoma Cell ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cell ◽  
Glioblastoma Cell Lines

Gastrin inhibits motility, decreases cell death levels and increases proliferation in human glioblastoma cell lines

1998 ◽  
Vol 37 (3) ◽  
pp. 373-382 ◽  
Author(s):  
Christophe De Hauwer ◽  
Isabelle Camby ◽  
Francis Darro ◽  
Isabelle Migeotte ◽  
Christine Decaestecker ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Glioblastoma Cell ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cell ◽  
Glioblastoma Cell Lines

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

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 222 ◽  
Author(s):  
María Fuentes-Baile ◽  
Daniel Bello-Gil ◽  
Elizabeth Pérez-Valenciano ◽  
Jesús M. Sanz ◽  
Pilar García-Morales ◽  
...  
Keyword(s):  
Cell Death ◽  
Magnetic Nanoparticles ◽  
Tumor Cells ◽  
Cell Lines ◽  
Epigenetic Therapy ◽  
Acid Oxidase ◽  
Glioblastoma Cell ◽  
Amino Acid Oxidase ◽  
Apoptosis Pathway ◽  
Glioblastoma Cell Lines

D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids generating hydrogen peroxide, a potential producer of reactive oxygen species. In this study, we used a CLytA-DAAO chimera, both free and bound to magnetic nanoparticles, against colon carcinoma, pancreatic adenocarcinoma, and glioblastoma cell lines. We found that the enzyme induces cell death in most of the cell lines tested and its efficiency increases significantly when it is immobilized in nanoparticles. We also tested this enzyme therapy in non-tumor cells, and we found that there is not cell death induction, or it is significantly lower than in tumor cells. The mechanism triggering cell death is apparently a classical apoptosis pathway in the glioblastoma cell lines, while in colon and pancreatic carcinoma cell lines, CLytA-DAAO-induced cell death is a necrosis. Our results constitute a proof of concept that an enzymatic therapy, based on magnetic nanoparticles-delivering CLytA-DAAO, could constitute a useful therapy against cancer and besides it could be used as an enhancer of other treatments such as epigenetic therapy, radiotherapy, and treatments based on DNA repair.

scholarly journals Cell Death Mechanisms Induced by CLytA-DAAO Chimeric Enzyme in Human Tumor Cell Lines

2020 ◽  
Vol 21 (22) ◽  
pp. 8522
Author(s):  
María Fuentes-Baile ◽  
Pilar García-Morales ◽  
Elizabeth Pérez-Valenciano ◽  
María P. Ventero ◽  
Jesús M. Sanz ◽  
...  
Keyword(s):  
Cell Death ◽  
Colorectal Carcinoma ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Carcinoma Cell ◽  
Glioblastoma Cell ◽  
Amino Acid Oxidase ◽  
Carcinoma Cell Lines ◽  
Mitochondrial Membrane Depolarization ◽  
Glioblastoma Cell Lines

The combination of the choline binding domain of the amidase N-acetylmuramoyl-L-alanine (CLytA)-D-amino acid oxidase (DAAO) (CLytA-DAAO) and D-Alanine induces cell death in several pancreatic and colorectal carcinoma and glioblastoma cell lines. In glioblastoma cell lines, CLytA-DAAO-induced cell death was inhibited by a pan-caspase inhibitor, suggesting a classical apoptotic cell death. Meanwhile, the cell death induced in pancreatic and colon carcinoma cell lines is some type of programmed necrosis. In this article, we studied the mechanisms that trigger CLytA-DAAO-induced cell death in pancreatic and colorectal carcinoma and glioblastoma cell lines and we acquire a further insight into the necrotic cell death induced in pancreatic and colorectal carcinoma cell lines. We have analyzed the intracellular calcium mobilization, mitochondrial membrane potential, PARP-1 participation and AIF translocation. Although the mitochondrial membrane depolarization plays a crucial role, our results suggest that CLytA-DAAO-induced cell death is context dependent. We have previously detected pancreatic and colorectal carcinoma cell lines (Hs766T and HT-29, respectively) that were resistant to CLytA-DAAO-induced cell death. In this study, we have examined the putative mechanism underlying the resistance in these cell lines, evaluating both detoxification mechanisms and the inflammatory and survival responses. Overall, our results provide a better understanding on the cell death mechanism induced by CLytA-DAAO, a promising therapy against cancer.

scholarly journals The Chk1 inhibitor SAR-020106 sensitizes human glioblastoma cells to irradiation, to temozolomide, and to decitabine treatment

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Ina Patties ◽  
Sonja Kallendrusch ◽  
Lisa Böhme ◽  
Eva Kendzia ◽  
Henry Oppermann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Multimodal Treatment ◽  
Neural Progenitor Cells ◽  
Glioblastoma Cell ◽  
Chk1 Inhibitor ◽  
Induction Of Apoptosis ◽  
Glioblastoma Cell Lines

Abstract Background Glioblastoma is the most common and aggressive brain tumour in adults with a median overall survival of only 14 months after standard therapy with radiation therapy (IR) and temozolomide (TMZ). In a novel multimodal treatment approach we combined the checkpoint kinase 1 (Chk1) inhibitor SAR-020106 (SAR), disrupting homologue recombination, with standard DNA damage inducers (IR, TMZ) and the epigenetic/cytotoxic drug decitabine (5-aza-2′-deoxycitidine, 5-aza-dC). Different in vitro glioblastoma models are monitored to evaluate if the impaired DNA damage repair may chemo/radiosensitize the tumour cells. Methods Human p53-mutated (p53-mut) and -wildtype (p53-wt) glioblastoma cell lines (p53-mut: LN405, T98G; p53-wt: A172, DBTRG) and primary glioblastoma cells (p53-mut: P0297; p53-wt: P0306) were treated with SAR combined with TMZ, 5-aza-dC, and/or IR and analysed for induction of apoptosis (AnnexinV and sub-G1 assay), cell cycle distribution (nuclear PI staining), DNA damage (alkaline comet or gH2A.X assay), proliferation inhibition (BrdU assay), reproductive survival (clonogenic assay), and potential tumour stem cells (nestinpos/GFAPneg fluorescence staining). Potential treatment-induced neurotoxicity was evaluated on nestin-positive neural progenitor cells in a murine entorhinal-hippocampal slice culture model. Results SAR showed radiosensitizing effects on the induction of apoptosis and on the reduction of long-term survival in p53-mut and p53-wt glioblastoma cell lines and primary cells. In p53-mut cells, this effect was accompanied by an abrogation of the IR-induced G2/M arrest and an enhancement of IR-induced DNA damage by SAR treatment. Also TMZ and 5-aza-dC acted radioadditively albeit to a lesser extent. The multimodal treatment achieved the most effective reduction of clonogenicity in all tested cell lines and did not affect the ratio of nestinpos/GFAPneg cells. No neurotoxic effects were detected when the number of nestin-positive neural progenitor cells remained unchanged after multimodal treatment. Conclusion The Chk1 inhibitor SAR-020106 is a potent sensitizer for DNA damage-induced cell death in glioblastoma therapy strongly reducing clonogenicity of tumour cells. Selectively enhanced p53-mut cell death may provide stronger responses in tumours defective of non-homologous end joining (NHEJ). Our results suggest that a multimodal therapy involving DNA damage inducers and DNA repair inhibitors might be an effective anti-tumour strategy with a low risk of neurotoxicity.

scholarly journals Fractionated radiotherapy is the main stimulus for the induction of cell death and of Hsp70 release of p53 mutated glioblastoma cell lines

2014 ◽  
Vol 9 (1) ◽  
pp. 89 ◽  
Author(s):  
Yvonne Rubner ◽  
Carolin Muth ◽  
Annedore Strnad ◽  
Anja Derer ◽  
Renate Sieber ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Glioblastoma Cell ◽  
Fractionated Radiotherapy ◽  
Glioblastoma Cell Lines
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