Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD®immunomodulatory drug pomalidomide
| Autor: | Paul G. Richardson, Deepika Sharma Das, Arghya Ray, Dharminder Chauhan, Kenneth C. Anderson, Mohit Trikha, Yan Song |
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| Rok vydání: | 2015 |
| Předmět: |
Ubiquitin-Protein Ligases
Transplantation Heterologous Down-Regulation Angiogenesis Inhibitors Apoptosis Mice SCID Pharmacology Article Lactones Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Pyrroles RNA Small Interfering Multiple myeloma Adaptor Proteins Signal Transducing Lenalidomide Bortezomib business.industry Cereblon Drug Synergism Hematology medicine.disease Pomalidomide Thalidomide Proteasome Drug Resistance Neoplasm Caspases Proteasome inhibitor Poly(ADP-ribose) Polymerases Multiple Myeloma business Proteasome Inhibitors Peptide Hydrolases medicine.drug |
| Zdroj: | British Journal of Haematology. 171:798-812 |
| ISSN: | 0007-1048 |
| DOI: | 10.1111/bjh.13780 |
| Popis: | The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. CRBN-siRNA attenuates marizomib plus pomalidomide-induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour-associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on-going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM. |
| Databáze: | OpenAIRE |
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