title: Rocaglamide breaks TRAIL-resistance in human multiple myeloma and acute T-cell leukemia in vivo in a mouse xenogtraft model.
abstract: Multiple myeloma (MM) is an incurable malignancy by the presently known therapies. TRAIL is a promising anticancer agent that virtually not shows any toxicity to normal cells. We have recently carried out clinical trials with a human circularly permuted TRAIL, CPT, against MM saw a partial response in approximate 20-30% of patients. In the current study, we investigated the cause of CPT resistance and revealed that the majority of the MM patients express elevated levels of c-FLIP. Knockdown of c-FLIP expression by siRNA alone was sufficient to increase CPT-mediated apoptosis in a CPT-resistant human MM cell line U266. To overcome CPT resistance, we investigated the combination of CPT with Rocaglamides(s) in MM which has been shown to inhibit c-FLIP expression in vitro. We show that Rocaglamide(s) overcomes CPT resistance in U266 in vitro and significant increases in anti-tumor efficacies of CPT in mice xenografted with U266. Similar results were also obtained in mice xenografted with the CPT-resistant human acute T-cell leukemia cell line Molt-4. Our study suggests that the combination of Rocaglamide(s) with CPT may provide a more efficient treatment against myeloma and leukemia.
authors.affiliation: Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumorimmunology 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: D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001572:Benzofurans; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C107772:rocaglamide
keywords: Apoptosis; Leukemia; Myeloma; Rocaglamide; TRAIL; c-FLIP