In:
British Journal of Haematology, Wiley, Vol. 162, No. 5 ( 2013-09), p. 657-669
Abstract:
Targeting the proteasome system with bortezomib ( BTZ ) results in anti‐tumour activity and potentiates the effects of chemotherapy/biological agents in multiple myeloma and B‐cell lymphoma. Carfilzomib ( CFZ ) is a more selective proteasome inhibitor that is structurally distinct from BTZ . In an attempt to characterize its biological activity, we evaluated CFZ in several lymphoma pre‐clinical models. Rituximab‐sensitive cell lines ( RSCL ), rituximab‐resistant cell lines ( RRCL ), and primary tumour cells derived from B‐cell lymphoma patients were exposed to CFZ or BTZ . Cell viability and changes in cell cycle were determined. Western blots were performed to detect PARP ‐cleavage and/or changes in Bcl‐2 ( BCL 2) family members. CFZ was 10 times more active than BTZ and exhibited dose‐ and time‐dependent cytotoxicity. CFZ exposure induced apoptosis by upregulation of Bak ( BAK 1) and subsequent PARP cleavage in RSCL and RRCL ; it was also partially caspase‐dependent. CFZ induced G2/M phase cell cycle arrest in RSCL . CFZ demonstrated the ability to overcome resistance to chemotherapy in RRCL and potentiated the anti‐tumour activity of chemotherapy agents. Our data suggest that CFZ is able to overcome resistance to chemotherapeutic agents, upregulate pro‐apoptotic proteins to promote apoptosis, and induce G2/M cell cycle arrest in lymphoma cells. Our pre‐clinical data supports future clinical evaluation of CFZ in B‐cell lymphoma.
Type of Medium:
Online Resource
ISSN:
0007-1048
,
1365-2141
DOI:
10.1111/bjh.2013.162.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
1475751-5
