Mechanism of Wogonin-mediated sensitization of HTLV-1-associated ATL cells to TRAIL-induced apoptosis

Abstract

Targeting apoptosis pathways is one of the key strategies for cancer treatment. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of tumor cells but not in non-malignant cells. Therefore, TRAIL is a promising anti-cancer agent. However, approximately 50 % of cancers are resistant to TRAIL, including the human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia (ATL). So far various treatment strategies are offered to ATL patients, but the mortality of ATL remains very high due to apoptosis resistance. Our group has previously shown that Wogonin, derived from the Traditional Chinese Medicine (TCM) plant Huang-Qin (Scutellaria baicalensis Georgi), can sensitize TRAIL-mediated apoptosis in primary AML (acute myeloid leukemia) cells. Importantly, Wogonin does not affect the viability of peripheral blood T cells derived from healthy donors. However, the mechanisms of Wogonin-mediated sensitization of TRAIL-induced apoptosis are still not known. In this study, HTLV-1-associated ATL cell lines SP, MT-2 and MT-4 were used to investigate resensitization resistant tumor cells to TRAIL-induced apoptosis. We found that Wogonin sensitized TRAIL-induced apoptosis in HTLV-1-associated ATL cells by down-regulation of caspase-8 inhibitory protein (FLICE)-like inhibitory protein (c-FLIP) expression at the transcriptional level. In addition, Wogonin enhanced the expression of TRAIL receptor 2 (TRAIL-R2) via up-regulation of p53. Increased p53 expression was due to inhibition of p53 negative regulator MDM2 at the transcriptional level. We also demonstrated that structurally related natural flavones, e.g. Apigenin and Chrysin, inhibited c-FILP at the transcriptional level and increased TRAIL-R2 expression via up-regulation of p53 through suppression of p53 negative regulator MDM2 in HTLV-1-associated ATL cells. Our study raises the possibility to develop Wogonin, Apigenin and Chrysin as TRAIL adjuvants for treatment of ATL and other types of tumors.