TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages.
BMC Cancer
; 13: 140, 2013 Mar 22.
Article
em En
| MEDLINE
| ID: mdl-23517112
ABSTRACT
BACKGROUND:
Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments.METHODS:
Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM.RESULTS:
Treatment with 0.5-1 µM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10-20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells.CONCLUSION:
The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pleurais
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Apoptose
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Proteínas Proto-Oncogênicas c-akt
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Inibidores de Proteassoma
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Proteína de Sequência 1 de Leucemia de Células Mieloides
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Neoplasias Pulmonares
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Mesotelioma
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article