Open AccessProlonged low‐dose administration of the cyclooxygenase‐2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts
Author(s) -
Kaneko Michio,
Kaneko Setsuko,
Suzuki Kenshi
Publication year - 2009
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2009.01280.x
Subject(s) - celecoxib , apoptosis , irinotecan , angiogenesis , medicine , pharmacology , neuroblastoma , cyclooxygenase , vascular endothelial growth factor , cox 2 inhibitor , cancer research , endocrinology , cancer , chemistry , biology , cell culture , enzyme , colorectal cancer , biochemistry , vegf receptors , genetics
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‐2 nu , and TS‐N‐5 nu . 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. ( Cancer Sci 2009; 00: 000–000)