Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts.
Cyclooxygenase (COX)-2 is overexpressed in many human tumors including neuroblastoma (NB) and promotes tumor progression. We evaluated the antitumor effect of irinotecan (CPT-11) treatment combined with prolonged very low-dose administration of celecoxib, a selective COX-2 inhibitor, against three human NB xenografts, TNB9, TS-N-2nu, and TS-N-5nu. In addition, the effects of the celecoxib-combined treatment were examined on tumor cell proliferation, apoptosis, angiogenesis, and expression of vascular endothelial growth factor and apoptosis-related proteins in xenografts. Celecoxib administered daily at 5 mg/kg body weight/day could not prevent the growth of any of the NB xenografts. However, the combination of daily low-dose CPT-11 (5.9 mg/kg body weight/day) and simultaneous very low-dose celecoxib resulted in highly significant suppression of tumor growth in all three xenografts (P < 0.001) compared not only with low-dose CPT-11 therapy alone but also with the combination therapy of intermittent conventional-dose CPT-11 (59 mg/kg body weight) and celecoxib accompanied by decreased proliferation and increased induction of apoptosis in tumor cells. Induction of apoptosis by CPT-11 with and without celecoxib was associated with the up-regulation of Bax expression and the down-regulation of Bcl-2 expression. The enhanced antitumor effect of the combination of the two drugs against the NB xenografts might be partially COX-2-independent and was probably mediated through multiple factors including diminished expression of VEGF and activation of the caspase-dependent mitochondrial apoptosis pathway. These findings demonstrate that prolonged low-dose CPT-11 treatment combined with very low-dose celecoxib shows promising antitumor activity through the blockage of multiple critical targets related to NB tumor cell survival and proliferation.
Kaneko
Michio
M
Department of Pediatric Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan. mkaneko@md.tsukuba.ac.jp
Kaneko
Setsuko
S
Suzuki
Kenshi
K
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000077146:Irinotecan; D000068579:Celecoxib; D002166:Camptothecin