title: Leflunomide reduces proliferation and induces apoptosis in neuroblastoma cells in vitro and in vivo.
abstract: Leflunomide as an immunosuppressive drug is generally used in the treatment of rheumatoid arthritis. It inhibits DHODH (dihydroorotate dehydrogenase ), which is one of the essential enzymes in the de novo pyrimidine biosynthetic pathway. Here we showed that leflunomide significantly reduced cell proliferation and self-renewal activity. Annexin V-FITC/PI staining assay revealed that leflunomide induced S-phase cell cycle arrest, and promoted cell apoptosis. In vivo xenograft study in SCID mice showed that leflunomide inhibited tumor growth and development. We also observed that DHODH was commonly expressed in neuroblastoma. When treated with leflunomide, the neuroblastoma cell lines BE(2)-C, SK-N-DZ, and SK-N-F1 showed dramatic inhibition of DHODH at mRNA and protein levels. Considering the favorable toxicity profile and the successful clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in neuroblastoma.
authors: State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China ; College of Life Science, Southwest University, Chongqing, China.
authors: Shunqin
authors: S
authors: Zhu
authors: Xiaomin
authors: X
authors: Yan
authors: Zhonghuai
authors: Z
authors: Xiang
authors: Han-Fei
authors: HF
authors: Ding
authors: Hongjuan
authors: H
authors: Cui
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D007555:Isoxazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide
references: N Engl J Med. 2005 Mar 17;352(11):1157-8
references: 15784677
references: Med Pediatr Oncol. 1996 Dec;27(6):534-9
references: 8888813
references: Biochem Pharmacol. 1996 Aug 23;52(4):527-34
references: 8759024
references: Immunotherapy. 2010 Sep;2(5):637-50
references: 20874647
references: J Immunol. 2007 Nov 15;179(10):6479-84
references: 17982036
references: Biochem J. 1998 Dec 1;336 ( Pt 2):299-303
references: 9820804
references: Science. 2011 Sep 16;333(6049):1569-71
references: 21921174
references: J Pediatr Surg. 1968 Feb;3(1):106-10
references: 5655555
references: Transpl Infect Dis. 2007 Mar;9(1):28-32
references: 17313468
references: Biochem Pharmacol. 1999 Nov 1;58(9):1405-13
references: 10513984
references: Arthritis Rheum. 2009 Mar;60(3):669-77
references: 19248091
references: Nature. 2011 Mar 24;471(7339):518-22
references: 21430780
references: Mol Microbiol. 2008 Apr;68(1):37-50
references: 18312275
references: J Biol Chem. 1998 Aug 21;273(34):21682-91
references: 9705303
references: Leukemia. 2008 Mar;22(3):635-8
references: 17805332
references: J Pharmacol Exp Ther. 1995 Nov;275(2):1043-9
references: 7473131
references: Trends Mol Med. 2005 Sep;11(9):430-7
references: 16098809
references: J Biol Chem. 2004 Aug 6;279(32):33035-8
references: 15096496
references: Neoplasia. 2010 Jun;12(6):464-75
references: 20563249
references: Mol Cancer Ther. 2009 Feb;8(2):366-75
references: 19174558
references: Nat Rev Cancer. 2003 Mar;3(3):203-16
references: 12612655
references: Pediatr Transplant. 2010 Feb;14(1):145-50
references: 19344337
references: J Biol Chem. 2006 Nov 10;281(45):34696-704
references: 16982619
references: Gene. 2000 Oct 31;257(2):209-22
references: 11080587
references: Bone Marrow Transplant. 2004 Dec;34(12):1071-5
references: 15489872
references: Biochem Pharmacol. 1995 Sep 7;50(6):861-7
references: 7575649
references: Cancer Res. 1986 Oct;46(10):5014-9
references: 3019518
references: Clin Cancer Res. 1997 Jul;3(7):1167-77
references: 9815796
references: Clin Cancer Res. 2012 Jan 15;18(2):417-31
references: 22072733
references: J Neurosci Methods. 1987 Sep;21(1):9-16
references: 3309485
references: Klin Padiatr. 2006 May-Jun;218(3):180-4
references: 16688677