Cytotoxicity and Target Modulation in Pediatric Solid Tumors by the Proteasome Inhibitor Carfilzomib.
Curr Cancer Drug Targets
; 21(9): 804-811, 2021.
Article
em En
| MEDLINE
| ID: mdl-33949932
ABSTRACT
BACKGROUND:
Most children with recurrent metastatic solid tumors have high mortality rates. Recent studies have shown that proteasome inhibition leads to effective tumor killing in cells that have acquired treatment resistance and metastatic properties.OBJECTIVE:
The purpose of this study was to test the potential of Carfilzomib (CFZ), a proteasome inhibitor, in refractory pediatric solid tumors which is currently unknown.METHODS:
A panel of pediatric solid tumor cell lines, including neuroblastoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma and atypical teratoid rhabdoid tumor (ATRT), was used to evaluate the cytotoxic and proteasomal inhibitory effects of CFZ. A drug scheduling experiment was performed to determine the optimal dose and time to obtain effective cell killing. Combination studies of CFZ with chemotherapeutic drugs of different classes were performed to determine the extent of synergy.RESULTS:
CFZ showed effective cytotoxicity against all cell lines tested (mean IC50 = 7nM, range = 1-20nM) and activity in a fluorophore-tagged cell-based proteasome assay. Drug scheduling experiments showed that the minimum exposure of 4-8 hours/day is needed for effective cumulative killing. CFZ, when combined with chemotherapeutic drugs of different classes, synergistically enhanced the extent of cell death.CONCLUSION:
CFZ showed cytotoxic activity against all the solid pediatric cancer cell lines tested. This study provides initial in vitro data on the potential of CFZ to treat pediatric solid tumors and supports further investigations into the components of drug scheduling, biological correlates and drug combinations for future early phase clinical trials in children.Palavras-chave
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteassoma
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Curr Cancer Drug Targets
Ano de publicação:
2021
Tipo de documento:
Article