title: Synthetic flavanones augment the anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of Silesia, Katowice, Jordana 19, Zabrze 41-808, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Szliszka
authors.forename: Edyta
authors.initials: E
authors.lastname: Kostrzewa-Susłow
authors.forename: Joanna
authors.initials: J
authors.lastname: Bronikowska
authors.forename: Dagmara
authors.initials: D
authors.lastname: Jaworska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janeczko
authors.forename: Zenon P
authors.initials: ZP
authors.lastname: Czuba
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krol
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D044950:Flavanones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053218:Receptors, Death Domain / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D044950:Flavanones; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand