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Updated: Mar 9, 2026
Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
Rocaglamide breaks TRAIL-resistance in human multiple myeloma and acute T-cell leukemia in vivo in a mouse xenogtraft
Yin Wu1, Marco Giaisi2, Rebecca Köhler2
1Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China.
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.
Insights
This study found that elevated c-FLIP levels cause resistance to CPT therapy in multiple myeloma. Combining Rocaglamide(s) with CPT overcomes this resistance, enhancing anti-tumor effects in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Multiple myeloma (MM) remains an incurable cancer despite current therapies.
- TRAIL-based therapies, like CPT, show promise but face resistance issues in MM.
- Elevated c-FLIP expression is identified as a key mechanism of CPT resistance in MM.
Purpose of the Study:
- To investigate the mechanisms of CPT resistance in multiple myeloma.
- To evaluate the efficacy of combining CPT with Rocaglamide(s) to overcome CPT resistance.
- To assess the therapeutic potential of this combination in preclinical models of MM and leukemia.
Main Methods:
- Investigated c-FLIP expression in MM patients and cell lines.
- Utilized siRNA to knockdown c-FLIP expression in U266 MM cells.
- Assessed the in vitro and in vivo efficacy of CPT alone and in combination with Rocaglamide(s).
- Tested the combination therapy in U266 (MM) and Molt-4 (leukemia) xenograft mouse models.
Main Results:
- High c-FLIP levels were observed in the majority of MM patients, correlating with CPT resistance.
- siRNA-mediated knockdown of c-FLIP sensitized CPT-resistant U266 cells to CPT-induced apoptosis.
- Rocaglamide(s) demonstrated the ability to overcome CPT resistance in U266 cells in vitro.
- The combination of Rocaglamide(s) and CPT significantly enhanced anti-tumor efficacy in both MM and leukemia xenograft models.
Conclusions:
- Elevated c-FLIP is a critical factor in CPT resistance in multiple myeloma.
- Rocaglamide(s) effectively overcomes CPT resistance by inhibiting c-FLIP.
- The combination of Rocaglamide(s) and CPT presents a promising therapeutic strategy for treating myeloma and leukemia.
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