title: Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that kills various tumor cells without damaging normal tissues. However, many cancers remain resistant to TRAIL. To overcome TRAIL resistance, combination therapies using sensitizers of the TRAIL pathway would be an efficacious approach. To investigate potential sensitizers of TRAIL-induced apoptosis, we used TRAIL-resistant human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) cells as a model system. So far, HTLV-1-associated ATL is incurable by presently known therapies. Here, we show that wogonin and the structurally related natural flavones apigenin and chrysin break TRAIL resistance in HTLV-1-associated ATL by transcriptional down-regulation of c-FLIP, a key inhibitor of death receptor signaling, and by up-regulation of TRAIL receptor 2 (TRAIL-R2). This effect is mediated through transcriptional inhibition of the p53 antagonist murine double minute 2 (Mdm2), leading to an increase in p53 levels and, consequently, to up-regulation of the p53 target gene TRAIL-R2. We also show that these flavones can sensitize to TNFα- and CD95-mediated cell death. Furthermore, we show that wogonin, apigenin, and chrysin also enhance TRAIL-mediated apoptosis in other human cancer cell lines including breast cancer cell line MDA-MB-231, colon cancer cell line HT-29, hepatocellular carcinoma cell line HepG2, melanoma cell line SK-MEL-37, and pancreatic carcinoma cell line Capan-1 by the same mechanism. Thus, our study suggests the potential use of these flavones as an adjuvant for TRAIL-mediated anticancer therapy.
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Polier
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumor Immunology Program (D030), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. Electronic address: m.li-weber@dkfz-heidelberg.de.
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000906:Antibodies / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044950:Flavanones / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015458:Leukemia, T-Cell / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D019014:fas Receptor / Q000276:immunology
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D001688:Biological Products; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D044950:Flavanones; D047309:Flavones; D005419:Flavonoids; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C043561:chrysin; D047310:Apigenin; D051736:Proto-Oncogene Proteins c-mdm2; C085514:wogonin
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