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Bortezomib Inhibits Nuclear Factor-B–Dependent Survival and Has Potent In vivo Activity in Mesothelioma

Authors' Affiliations: ¹ Falck Division of Medical Oncology, Niguarda, Ca' Granda Hospital, Milan, Italy; ² Oncology, Biology Department, Nerviano Medical Sciences, 20014 Nerviano, Italy; ³ Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island; ⁴ Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biology Center, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy; ⁵ Center for Cancer Research and Cell Biology, Queen's University, Belfast, N. Ireland, United Kingdom; and ⁶ Local Health Unit 11, Vercelli, Italy

Requests for reprints: Luciano Mutti, Lab of Clinical Oncology, Department of Medicine, Local Health Unit 11 Vercelli P. le Lora 1 13011 Borgosesia (VC), Italy. Phone: 39-0163-203-7240; E-mail: luciano.mutti{at}hotmail.it.

Purpose: Purpose of this study has been the assessment of nuclear factor-B (NF-B) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-B activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm.

Experimental Design: In HMC and MMe cells, NF-B nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor- (TNF-). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated.

Results: Here, we show that NF-B activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-B activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo.

Conclusions: Inhibition of NF-B constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe.

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