1. Rocaglamide breaks TRAIL-resistance in human multiple myeloma and acute T-cell leukemia in vivo in a mouse xenogtraft model
- Author
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Peter H. Krammer, Rebecca Köhler, Yin Wu, Min Li-Weber, Marco Giaisi, and Wen Ming Chen
- Subjects
0301 basic medicine ,endocrine system ,Cancer Research ,endocrine system diseases ,CASP8 and FADD-Like Apoptosis Regulating Protein ,TNF-Related Apoptosis-Inducing Ligand ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Rocaglamide ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Medicine ,heterocyclic compounds ,neoplasms ,Multiple myeloma ,Benzofurans ,Gene knockdown ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,Recombinant Proteins ,digestive system diseases ,Leukemia ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Toxicity ,Immunology ,Cancer research ,Multiple Myeloma ,business - 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.
- Published
- 2017