Inhibition of human neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor.
Neuroblastomas constitute about 10% of childhood cancers and are responsible for 15% of pediatric cancer mortality. We evaluated the efficacy and the mechanism of cell death induced by CAY10404, a selective cyclooxygenase-2 (Cox-2) inhibitor in four human neuroblastoma cell lines (SH-EP, SH-SY5Y, SK-N-MC and MSN). Treatment with CAY10404 in the range of 15-115 microM revealed a dose-dependent decrease in cell number and an average IC50 (inhibitory concentration 50%) of 60 microM. About 20-30% of the cells were terminal deoxynucleotidyltransferase-mediated UTP nick-end-labeling (TUNEL) positive 48 h after treatment. Western blot analysis of CAY10404-treated cells showed poly(ADP-ribose) polymerase (PARP) cleavage and cleaved caspase-3 signifying caspase activity and apoptotic cell death. Inhibitor-of-apoptosis proteins including X-linked inhibitor-of-apoptosis protein (XIAP) and survivin did not change significantly after CAY10404 treatment. Fluorescence activated cell sorter (FACS) analysis performed in two different cell lines 48 h following CAY10404 treatment showed a reduction in the number of cells in the G1 phase of the cell cycle and an increase in the number of cells in the G2 phase. When radioresistant SH-EP cells were treated with CAY10404, a 49% decrease in cell viability was observed relative to DMSO-treated cells; pretreatment with CAY10404 followed by ortho-voltage irradiation further enhanced cell death (58%) suggesting radiosensitization by CAY10404.
Parashar
Bhupesh
B
Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY 10461, USA.
Latha Shankar
Sai
S
O'Guin
Kathleen
K
Butler
James
J
Vikram
Bhadrasain
B
Shafit-Zagardo
Bridget
B
D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D000077022:Survivin; D013997:Time Factors; D051636:X-Linked Inhibitor of Apoptosis Protein
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; C107489:BIRC5 protein, human; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D007555:Isoxazoles; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011838:Radiation-Sensitizing Agents; D013450:Sulfones; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human