Background : The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we describe the characterization of a novel agonistic mAb (AY4) against human DR4 and apoptosis through reactive oxygen species (ROS) production in head and neck cancer model.

Methods : The effects of AY4 in head and neck cell lines (KB, SNU899, HN9, FaDu) was studied on apoptosis using MTT assy, TUNEL, Annexin V assay and western blotting and was examed on the production of reactive oxygen species with DCFDA staining, intracellular signaling and animal model. In addition, we analyzed the anticancer effect of AY4 in nude mice xenograft model. In addition, drug toxicity (embryotoxicity and neurotoxicity) of AY4 were investigated in vivo zebrafish model.

Results: The DR4 was expressed in head and neck cancer cell lines by Flow cytometry (FACS) and western blotting. AY4 inhibited cell growth in KB and HN9 excluding SNU899 and FaDu and caused cell death via caspase-dependent apoptosis. The apoptotic cell death by AY4 decreased by N-acetylcysteine (NAC), an antioxidant, suggesting ROS generation involved in the cell death. Moreover, NAC and AY4 cotreatment augmented the reduced expression of antiapoptotic molecules, Bcl-XL and XIAP. In vivo administration of AY4 significantly inhibited tumor growth of head and neck cancer preestablished in athymic nude mice. In addition, in a zebrafish model used for toxicity testing, a considerable dose of AY4 did not result in embryotoxicity or neurotoxicity.

Conclusion : Our results demonstrates the effect of AY4 on apoptosis and tumor inhibition via ROS production and provide potential use of AY4 as an anticancer therapeutic agent in head and neck cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4772. doi:10.1158/1538-7445.AM2011-4772

©2011 American Association for Cancer Research
2011