Targeting the proteasome in refractory pediatric leukemia cells: Characterization of effective cytotoxicity of carfilzomib Journal Article


Authors: Swift, L.; Jayanthan, A.; Ruan, Y.; Anderson, R.; Boklan, J.; Trippett, T.; Narendran, A.
Article Title: Targeting the proteasome in refractory pediatric leukemia cells: Characterization of effective cytotoxicity of carfilzomib
Abstract: Background: Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next-generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies. Objective: Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia. Methods: The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemia patient samples were investigated in vitro using the alamar blue cytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices. Results: In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells. Conclusions: Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies. © 2018, Springer Nature Switzerland AG.
Journal Title: Targeted Oncology
Volume: 13
Issue: 6
ISSN: 1776-2596
Publisher: Springer  
Date Published: 2018-12-01
Start Page: 779
End Page: 793
Language: English
DOI: 10.1007/s11523-018-0603-0
PROVIDER: scopus c2 - 30446871
PUBMED: 30446871
DOI/URL:
Notes: Targeted Oncol. -- Export Date: 2 January 2019 -- Article -- Source: Scopus C2 - 30446871
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  1. Tanya M Trippett
    110 Trippett