Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo

Abstract

Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2^specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.

Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo

“…Testing for synergistic or additive effects of combination therapy the data was done as described (Ponthan et al, 2007).…”

“…As a secondary antibody, the HRP-SuperPicture Polymer detection kit and matched isotype controls were used (Zymed Laboratories Inc., San Francisco, CA, USA). Bandeirea simplifolica (BS-1; Sigma-Aldrich) lectin was used to highlight murine endothelial cells as described previously (Segerstrom et al, 2006;Ponthan et al, 2007). Proliferation and apoptosis (cleaved caspase-3) were quantified at  400 magnification, whereas microvessel density (BS-1) was quantified at  200.…”

The novel melphalan prodrug J1 inhibits neuroblastoma growthin vitroandin vivo

“…As a control for nonspecific background staining, sections were incubated with rabbit IgG isotype control (Zymed). Biotinylated Bandeiraea simplicifolia (BS-1, L3759; Sigma-Aldrich) lectin was used for highlighting endothelial cells as described previously (17). Apoptosis and proliferation were assessed by counting the number of positively stained nuclei and the total number of tumor cells in three representative regions in three tumors from each treatment group at Â400 magnification.…”

Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

“…We and others have reported that cyclooxygenase (COX) inhibitors induce cell death and enhance chemosensitivity in neuroblastoma (Johnsen et al, 2004;Lau et al, 2007;Ponthan et al, 2007). COX inhibitors are non-steroidal anti-inflammatory drugs commonly used as analgesics and anti-inflammatory agents, but have also been shown to have anticancer properties (Thun et al, 2002).…”