title: Indomethacin enhances the cytotoxicity of recombinant human lymphotoxin alpha on tumor cells by suppressing NFkappaB signaling.
abstract: Indomethacin is widely used to treat inflammatory and prevent adverse events which frequently accrue in biotherapy. In phase I clinical trial of recombinant human lymphotoxin alpha (rhLTalpha), indomethacin was premedicated to alleviate chill and fever. However, it is unknown whether indomethacin influences the therapeutic efficacy of rhLTalpha. In this study we found that pre-treatment with low dose of indomethacin enhanced the cytotoxicity of rhLTalpha and/or cisplatin/adriamycin on human tumor cells. Further investigation demonstrated that indomethacin dose-dependently suppressed the activation of nuclear factor kappa B (NFkappaB) by inhibiting phosphorylation and degradation of IkappaBalpha. In addition, indomethacin decreased the expression of NFkappaB-regulated gene products involved in rhLTalpha-induced anti-apoptosis (XIAP, cFLIP and cIAP-1), which may explain its sensitization of tumor cells to rhLTalpha and/or cisplatin/adriamycin.
authors.affiliation: Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Shen
authors.forename: Tong
authors.initials: T
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tan
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wu
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Luochun
authors.initials: L
authors.lastname: Wang
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D007249:Inflammation; D020014:K562 Cells; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D011994:Recombinant Proteins; D007213:Indomethacin