Summary
Neuroblastoma is the most common solid tumor of infants and carries a poor prognosis especially in advanced stages. The present recommended therapies carry a high risk of side effects that is associated with long-term morbidity. We evaluated the efficacy of a low dose of the selective cyclooxygenase-2 inhibitor Nimesulide in preventing human Neuroblastoma tumor growth in Severe Combined Immune-deficient mice. Mice containing established tumors (SH-SY5Y cells) treated with 20 mg/kg Nimesulide every 4th day beginning on day 1 of cell injections resulted in a 65% reduction of tumor growth compared to the DMSO treated control mice (P<0.05) but did not significantly reduce tumor growth when Nimesulide was started once tumors reached 1cm. There was a reduction in the level of cyclooxygenase-2 protein and induction of effecter caspases in tumors treated with Nimesulide. However, there was no change in the levels of X-Inhibitor-of-Apoptosis-Protein, Smac/Diablo, or proteins of the PI3/Akt pathway following Nimesulide treatment. In Conclusion, low doses of Nimesulide can potentially be used as a chemopreventive agent for human Neuroblastoma.
Similar content being viewed by others
References
Smith WL, DeWitt DL, Garavito RM, (2000). Cyclooxygenases: structural, cellular and molecular biology Ann Rev Biochem 69:145–182
Gasparini G, Longo R, Sarmiento R, Morabito A, (2003). Inhibitors of cyclooxygenase 2: a new class of anticancer agents? Lancet Oncol 10:605–615
Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E, Taketo MM, Evans JF, (2001). Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor Cancer Res 61:1733–1740
Duperron C, Castonguay A, (1997). Chemopreventive efficacies of Aspirin and Sulindac against lung tumorogenesis in A/J mice Carcinogenesis 18:1001–1006
Grubbs CJ, Lubet RA, Koki AT, Leahy KM, Masferrer JL, Steele VE, Kelloff GJ, Hill DL, Seibert K, (2000). Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats Cancer Res 60:5599–5602
Nakatsugi S, Ohta T, Kawamori T, Mutoh M, Tanigawa T, Watanabe K, Sugie S, Sugimura T, Wakabayashi K, (2000). Chemoprevention by nimesulide, a selective cyclooxygenase-2 inhibitor, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland carcinogenesis in rats Jpn J Cancer Res 91:886–892
Parashar B, Latha Shankar S, O’Guin K, Butler J, Vikram B, Shafit-Zagardo B, (2005). Inhibition of human Neuroblastoma cell growth by CAY10404, a highly selective Cox-2 inhibitor J Neurooncol 71:141–8
Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjornsson B, Kogner P, (2004). Cyclooxygenase-2 is expressed in Neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo Cancer Res 64:7210–7215
Drazen JM, (2005). Cox-2 inhibitors – a lesson in unexpected problems NEJM 352:1131–1132
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA, (2005). Adenomatous polyp prevention on Vioxx (APPROVe) trial investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial NEJM 352:1092–1102
Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M, (2005). Adenoma prevention with celecoxib (APC) study investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention NEJM 352:1071–1080
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, (2000) VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group NEJM 343:1520–1528
Messmer K, Reynolds GP, (2005). An in vitro model of inflammatory neurodegeneration and its neuroprotection Neurosci Lett 388:39–44
Vincent AM, Feldman EL, Song DK, Jung V, Schild A, Zhang W, Imperiale MJ, Boulis NM, (2004). Adeno-associated viral-mediated insulin-like growth factor delivery protects motor neurons in vitro Neuromolecular Med 6:79–85
Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ, (2005). A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease J Biol Chem 280:22670–22678
Backman U, Svensson A, Christofferson R, (2002). Importance of vascular endothelial growth factor A in the progression of experimental Neuroblastoma Angiogenesis 5:267–274
Shankar SL, Mani S, O’Guin K, Kandimalla E, Agarwal S, Shafit-Zagardo B, (2001). Caspase independent and dependent death in human neural tumor cells following survivin inhibition J Neurochem 79:426–436
Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA, (2005). Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study Lancet 365:475–481
Kitamura T, Itoh M, Noda T, Matsuura M, Wakabayashi K, (2004). Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice Int J Cancer 109:576–580
Shaik MS, Chatterjee A, Singh M, (2004). Effect of a selective cyclooxygenase-2 inhibitor, nimesulide, on the growth of lung tumors and their expression of cyclooxygenase-2 and peroxisome proliferator- activated receptor-gamma Clin Cancer Res 10:1521–1529
Li XH, Li JJ, Zhang HW, Sun P, Zhang YL, Cai SH, Ren XD, (2003). Nimesulide inhibits tumor growth in mice implanted hepatoma: overexpression of Bax over Bcl-2 Acta Pharmacol Sin 24:1045–1050
Elder DJ, Halton DE, Hague A, Paraskeva C, (1997) Induction of apoptotic cell death in human colorectal carcinoma cell lines by cyclooxygenase-2 (Cox-2) selective non-steroidal anti-inflammatory drug: independence from Cox-2 protein expression Clin Cancer Res 3:1679–1683
Harada H, Grant S, (2003). Apoptosis regulators Rev Clin Exp Hematol 7:117–138
Dandekar DS, Lopez M, Carey RI, Lokeshwar BL, (2005). Cyclooxygenase-2 inhibitor celecoxib augments chemotherapeutic drug-induced apoptosis by enhancing activation of caspase-3 and -9 in prostate cancer cells Int J Cancer 115:484–492
Johnson AJ, Song X, Hsu A, Chen CS, (2001). Apoptosis signaling pathways mediated by cyclooxygenase-2 inhibitors in prostate cancer cells Adv Enzyme Regul 41:221–235
Baoping Y, Guoyong H, Jieping Y, Zongxue R, Hesheng L, (2004). Cyclooxygenase-2 inhibitor Nimesulide suppresses telomerase activity by blocking Akt/PKB activation in gastric cancer cell line Dig Dis Sci 49:948–953
Williams CS, Watson AM, Sheng H, Helou R, Shao J, DuBois RN, (2000) Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models Cancer Res 60:6045–6051
Nelson CM, Bissell MJ, (2005). Modeling dynamic reciprocity: Engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation Semin Cancer Biol 15(5):342–352
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Parashar, B., Shafit-Zagardo, B. Inhibition of human Neuroblastoma in SCID mice by low-dose of selective Cox-2 inhibitor Nimesulide. J Neurooncol 78, 129–134 (2006). https://doi.org/10.1007/s11060-005-9079-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-005-9079-8