The FGFR Inhibitor NVP-BGJ398 Induces NSCLC Cell Death by Activating Caspase-dependent Pathways as well as Caspase-independent Apoptosis.
BACKGROUND
Fibroblast growth factor receptors are expressed in diverse cell types. They play a critical role in tumor development. Their activation promotes cell-cycle progression, angiogenesis, and cell survival by induction/suppression of the expression of proteins involved.


METHODS
Non-small cell lung cancer (NSCLC) cells (line H1581) were treated with NVP-BGJ398 to evaluate effects on growth by western blot, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay and cell-cycle analysis.


RESULTS
NVP-BGJ398 induced cell death in H1581 cells by activating caspase-dependent mitochondrial and non-mitochondrial pathways. Caspase-independent apoptosis was also activated. Cells were found to be arrested in the G0/G1 phase. Furthermore, the expression of the tumor-suppressor gene programmed cell death 4 (PDCD4) was up-regulated with suppression of angiopoietin 2 (ANG2). This represents an additional mechanism by which NVP-BGJ389 inhibits tumor growth.


CONCLUSIONS
Various pathways induce apoptosis in NSCLC cells by employing NVP-BGJ398. These data reflect the potential of cancer treatment utilizing small FGFR inhibitors.
Research Unit of Gastroenterology, Center for Tumor and Immunobiology, Faculty of Medicine, University of Marburg, Marburg, Germany.
Antonia
A
Göke
Diabetes Center Marburg, Marburg, Germany.
Rüdiger
R
Göke
Medical Clinic 2, LMU University Hospital Munich, Munich, Germany.
Andrea
A
Ofner
Medical Clinic 2, LMU University Hospital Munich, Munich, Germany.
Andreas
A
Herbst
Research Unit of Gastroenterology, Center for Tumor and Immunobiology, Faculty of Medicine, University of Marburg, Marburg, Germany lankatbu@staff.uni-marburg.de.
Brigitte
B
Lankat-Buttgereit
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011743:Pyrimidines; C568950:infigratinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020169:Caspases
ANG2; NVP-BGJ398; PDCD4; Small molecule FGFR1 inhibitor; caspases