Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is considered as the most promising
anticancer agent in the TNF superfamily because of its selective cytotoxicity against
tumor cells versus normal primary cells. However, as more
tumor cells are reported to be resistant to TRAIL-mediated death, it is important to develop new therapeutic strategies to overcome this resistance.
Flavonoids have been shown to sensitize
cancer cells to TRAIL-induced apoptosis. The aim of this study was to examine the cytotoxic and apoptotic activities of TRAIL on HeLa
cancer cells in combination with two synthetic compounds: 6-hydroxyflavanone (6-HF) and its derivative 6-propionoxy-flavanone (6-PF) and to determine the mechanism by which the
flavanones overcome the TRAIL-resistance. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected by
annexin V-FITC fluorescence staining in flow cytometry and microscopy.
Death receptor (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression were analysed using flow cytometry. Mitochondrial membrane potential was evaluated using DePsipher staining by fluorescence microscopy. The synthetic
flavanones enhanced TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2
death receptor and reduction of mitochondrial membrane potential. Our study indicates that the 6-HF and 6-PF augmented the anticancer effects of TRAIL and confirm a potential use of
flavanones in TRAIL-based anticancer
therapy and prevention.