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Research Articles

TRAIL therapy in non–small cell lung cancer cells: sensitization to death receptor–mediated apoptosis by proteasome inhibitor bortezomib

Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands

Requests for reprints: Frank A.E. Kruyt, Department of Medical Oncology, CCA 2.36, VU University Medical Center, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-444-33-74; Fax: 31-20-444-38-44. E-mail: kruyt{at}vumc.nl

Abstract

Activation of the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor pathway is a promising therapeutic strategy to selectively eradicate cancer cells, including non–small cell lung cancer (NSCLC) cells. Recombinant human (rh) TRAIL/Apo-2L, a TRAIL-encoding adenovirus, and monoclonal antibodies directed against TRAIL receptors R1 and R2 were used to study cytotoxicity of TRAIL therapy in NSCLC cells. NSCLC cells showed differential sensitivity to TRAIL therapy, regardless of the agent used. Combination treatment of bortezomib and rhTRAIL led to synergistic apoptosis induction in NSCLC cell lines. Enhancement of rhTRAIL-induced apoptosis by bortezomib was caspase dependent, implicating extrinsic as well as intrinsic apoptosis activation, as shown by increased processing of caspase-8 as well as caspase-9, and could be abrogated completely by overexpression of caspase-8 inhibitor cytokine response modifier A (CrmA), and partially by overexpression of Bcl-2. Enhanced surface expression of TRAIL-R2, but also TRAIL-R1, was associated with bortezomib treatment, which is likely to contribute to the increased processing of caspase-8 in the combination treatment. Furthermore, TRAIL-induced activation of prosurvival transcription factor nuclear factor-B was prevented by cotreatment with bortezomib, which may contribute to the observed synergistic apoptosis induction. Our preclinical data indicate that combination therapy of TRAIL and bortezomib may be an effective strategy for NSCLC. [Mol Cancer Ther 2007;6(7):2103–12]

Grant support: The Netherlands Organization of Scientific Research ZonMW/NWO-AGIKO grant 920-03-290 (J. Voortman).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 8/07; revised 4/28/07; accepted 5/29/07.

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