Title:Cytotoxicity and Target Modulation in Pediatric Solid Tumors by the Proteasome Inhibitor Carfilzomib
Volume: 21
Issue: 9
关键词:
小儿肿瘤、实体瘤、卡非佐米、蛋白酶体抑制、神经母细胞瘤、ATRT、肉瘤。
摘要:
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.
