title: 5,7-Dihydroxyflavone Enhances the Apoptosis-Inducing Potential of TRAIL in Human Tumor Cells via Regulation of Apoptosis-Related Proteins.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for the treatment of cancer, because it preferentially induces apoptosis in numerous cancer cells with little or no effect on normal cells. 5,7-Dihydroxyflavone is a dietary flavonoid commonly found in many plants. Here we show that the combined treatment with 5,7-dihydroxyflavone and TRAIL at subtoxic concentrations induced strong apoptotic response in human hepatocarcinoma HepG2 cells, acute leukemia Jurkat T cells, and cervical carcinoma HeLa cells. We further investigated the mechanisms by which 5,7-dihydroxyflavone augments TRAIL-induced apoptosis in HepG2 cells. 5,7-Dihydroxyflavone up-regulated the expression of pro-apoptotic protein Bax, attenuated the expression of anti-apoptotic proteins Bcl-2, Mcl-1, and IAPs, and reduced the phosphorylation levels of Akt and STAT3, weakening the anti-apoptotic signals thus facilitating the process of apoptosis. Moreover, 5,7-dihydroxyflavone and TRAIL were well tolerated in mice, and the combination of 5,7-dihydroxyflavone and TRAIL reduced tumor burden in vivo in a HepG2 tumor xenograft model. Interestingly, 5,7-dihydroxyflavone-mediated sensitization to TRAIL-induced cell death was not observed in normal human hepatocytes L-O2. These results suggest that the 5,7-dihydroxyflavone in combination with TRAIL might be used for cancer prevention and/or therapy.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Traditional Chinese Medicine, 100 Shizi Street, Hongshang Road, Nanjing, Jiangsu 210028, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tingmei
authors.initials: T
authors.lastname: Ye
authors.forename: Xueting
authors.initials: X
authors.lastname: Cai
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.forename: Chunping
authors.initials: C
authors.lastname: Hu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Cao