Carfilzomib in combination with bortezomib enhances apoptotic cell death in b16-f1 melanoma cells

Min Seung Lee, So Hyun Lim, Ah Ran Yu, Chi Yeon Hwang, Insug Kang, Eui Ju Yeo

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Proteasome inhibitors, such as bortezomib (BZ) and carfilzomib (CFZ), have been sug-gested as treatments for various cancers. To utilize BZ and/or CFZ as effective therapeutics for treating melanoma, we studied their molecular mechanisms using B16-F1 melanoma cells. Flow cytom-etry of Annexin V-fluorescein isothiocyanate-labeled cells indicated apoptosis induction by treatment with BZ and CFZ. Apoptosis was evidenced by the activation of various caspases, including caspase 3, 8, 9, and 12. Treatment with BZ and CFZ induced endoplasmic reticulum (ER) stress, as indicated by an increase in eIF2α phosphorylation and the expression of ER stress-associated pro-teins, including GRP78, ATF6α, ATF4, XBP1, and CCAAT/enhancer-binding protein homologous protein. The effects of CFZ on ER stress and apoptosis were lower than that of BZ. Nevertheless, CFZ and BZ synergistically induced ER stress and apoptosis in B16-F1 cells. Furthermore, the com-binational pharmacological interactions of BZ and CFZ against the growth of B16-F1 melanoma cells were assessed by calculating the combination index and dose-reduction index with the CompuSyn software. We found that the combination of CFZ and BZ at submaximal concentrations could obtain dose reduction by exerting synergistic inhibitory effects on cell growth. Moreover, this drug combination reduced tumor growth in C57BL/6 syngeneic mice. Taken together, these results suggest that CFZ in combination with BZ may be a beneficial and potential strategy for melanoma treat-ment.

Original languageEnglish
Article number153
Pages (from-to)1-26
Number of pages26
JournalBiology
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2021

Keywords

  • Apoptosis
  • B16-F1 melanoma cells
  • Bortezomib
  • Carfilzomib
  • Proteasome inhibitor

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