TRAIL and Proteasome Inhibitors Combination Induces a Robust Apoptosis in Human Malignant Pleural Mesothelioma Cells Through Mcl-1 and Akt Protein Cleavages

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2013 Mar 23

PMID 23517112

Citations 8

Authors

Bao-Zhu Yuan

Joshua Chapman

Min Ding

Junzhi Wang

Binghua Jiang

Yon Rojanasakul

Steven H Reynolds

Affiliations

Soon will be listed here.

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.

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