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: Yijun Shen, Tong Yang, Jing Wang, Qing Xu, Rong Li, Wei Pan, Gang Li, Zheng Wang, Jingwei Tan, Jinsong Wu, Fang Wu, Luochun Wang, Yanjun Liu
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 9 Pg. 1428-33 (Sep 2007) ISSN: 1555-8576 [Electronic] United States
• PMID: 17873517 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Lymphotoxin-alpha
• NF-kappa B
• Recombinant Proteins
• Indomethacin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Indomethacin (pharmacology)
• Inflammation
• K562 Cells
• Lymphotoxin-alpha (pharmacology)
• Models, Biological
• NF-kappa B (metabolism)
• Neoplasms (drug therapy)
• Phosphorylation
• Recombinant Proteins (pharmacology)
• Signal Transduction