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Research Articles: Therapeutics, Targets, and Development

Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-B expression and proteasome activation in head and neck squamous carcinoma cell lines

Departments of ¹ Internal Medicine, ² Therapeutic Radiology and Oncology, ³ Biocenter, Division of Cell Biology; ⁴ Department of General Otorhinolaryngology, Innsbruck Medical University, ⁵ Institute of Analytical Chemistry and Radiochemistry, Leopold-Franzens University, Innsbruck, Austria; and ⁶ Myriad Pharmaceuticals Inc., Salt Lake City, Utah

Requests for reprints: Sergej Skvortsov, Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Phone: 43-512-504-25611; Fax: 43-512-504-25612. E-mail: Sergej.Skvortsov{at}i-med.ac.at

Abstract

This study aimed to characterize the antitumor activity of 5-Chloro-N-{2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl}-2-hydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 µmol/L with 17.16 ± 2.08%, 10.92 ± 1.22%, and 27.03 ± 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G₀-G₁ phase that was associated with the up-regulation of p21/WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-B (NF-B) and NF-B p65 phosphorylated at Ser⁵³⁶. The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-B is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer. [Mol Cancer Ther 2007;6(6):1898–908]

Grant support: Austrian National Bank Project 11681; Austrian Cancer Society/Tyrol. Work in the laboratory of Prof. Lukas A. Huber is supported by the Austrian Proteomics Platform within the Austrian Genome Program, Vienna, Austria, and the Special Research Program "Cell Proliferation and Cell Death in Tumors" (SFB021, Austrian Science Fund).

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.

Note: S. Skvortsov and I. Skvortsova contributed equally to this work.

⁷ Pleiman et al., manuscript in preparation.

⁸ http://www.matrixscience.com/

Received 11/15/06; revised 4/11/07; accepted 4/27/07.