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Farnesyltransferase Inhibitors and Human Malignant Pleural Mesothelioma: A First-Step Comparative Translational Study

¹ Department of Surgical Science, Division of General Thoracic Surgery, Catholic University, Rome, Italy; ² Department of Biology, University of Genoa; ³ Laboratory of Translational Research B (Lung Cancer), Department of Integrated Medical Oncology, National Cancer Institute, Genoa, Italy; ⁴ Center of Thoracic Surgery, University of Insubria, Varese, Italy; and ⁵ Pulmonary Rehabilitation, IRCCS San Raffaele, Rome, Italy

Requests for reprints: Patrizia Russo, Laboratory of Translational Research B (Lung Cancer), Department of Integrated Medical Oncology, National Cancer Institute, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. Phone: 39-0105600212; Fax: 39-0105600217; E-mail: patrizia.russo{at}istge.it.

It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor (TGF-), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non–small cell lung cancer cells A459. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336 BMS-214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF- secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin.

Key Words: FTIs • Mesothelioma • EGFR • translational research • apoptosis • cytotoxicity