Indomethacin enhances the cytotoxicity of recombinant human lymphotoxin alpha on tumor cells by suppressing NFkappaB signaling.
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.
Shen
Yijun
Y
Department of Genetic Engineering Development, Shanghai Fudan-Zhangjiang Bio-pharmaceutical Co., Ltd., Shanghai, China.
Yang
Tong
T
Wang
Jing
J
Xu
Qing
Q
Li
Rong
R
Pan
Wei
W
Li
Gang
G
Wang
Zheng
Z
Tan
Jingwei
J
Wu
Jinsong
J
Wu
Fang
F
Wang
Luochun
L
Liu
Yanjun
Y
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
D000970:Antineoplastic Agents; D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D011994:Recombinant Proteins; D007213:Indomethacin