Abstract 3724: Wogonin enhances tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo through H2O2-mediated downregulation of X-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis protein 1 and 2

Abstract

Abstract Numerous malignant cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity, limiting value of TRAIL as an antitumor therapeutics. Combination of TRAIL with other agents is a promising strategy to overcome TRAIL resistance. Wogonin (5, 7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of the medicinal herb Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. However, whether wogonin enhances TRAIL's antitumor activity in vivo has never been studied. In this study, we first found that wogonin sensitized a variety of cancer cells including A549, HeLa and SKOV3 to TRAIL-induced apoptosis, as indicated by increased annexin V staining and enhanced activation of caspase-8 and -3 in TRAIL and wogonin cotreated cells, whereas having marginal effect on non-transformed bronchial epithelial cells and cervical epithelial cells. Then the effect of combination of TRAIL and wogonin was tested in a xenografted tumor model with A549 cells in nude mice. The results show that wogonin greatly enhanced TRAIL-induced suppression of tumor growth, which was accompanied with increased apoptosis in tumor tissues determined by a terminal deoxynucleotidyl-transferase -mediated dUTP nick-end labeling (TUNEL) assay. The protein levels of X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) were markedly reduced in both cultured cells and xenografted tumor tissues with co-treatment of wogonin and TRAIL. The down-regulation of these antiapoptotic proteins was likely mediated through proteasomal degradation and involved intracellular H2O2, as wogonin robustly induced H2O2 accumulation in A549 cells and the reactive oxygen species scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins and suppressed cytotoxicity in cells co-treated with wogonin and TRAIL. These results provide important in vivo evidence supporting the application of wogonin as TRAIL sensitizer for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3724. doi:1538-7445.AM2012-3724