PRECLINICAL STUDIES Cell-growth and migration inhibition of human mesothelioma cells induced by 3-O-Methylfunicone from Penicillium pinophilum and cisplatin Elisabetta Buommino & Anna De Filippis & Rosario Nicoletti & Massimo Menegozzo & Simona Menegozzo & Maria Letizia Ciavatta & Antonietta Rizzo & Virginia Brancato & Maria Antonietta Tufano & Giovanna Donnarumma Received: 29 April 2011 /Accepted: 31 May 2011 /Published online: 9 June 2011 # Springer Science+Business Media, LLC 2011 Summary Malignant pleural mesothelioma is a fatal malig- nancy linked to asbestos exposure. The main challenge for mesothelioma treatment is to go beyond the drug resistance, in particular against cisplatin (CDDP), one of the most used chemotherapeutic drug. 3-O-methylfunicone (OMF) is a metabolite produced by the fungus Penicillium pinophilum; its antiproliferative properties have been previously studied in vitro. Particularly, OMF is able to inhibit mesothelioma cell motility. To improve the effects of CDDP by-passing the resistance of mesothelioma cells to this drug, in the present study we investigated the combined treatment of OMF with CDDP respectively in an established mesothelioma cell line (NCI) and primary mesothelioma cells (Mest). As compared to the effect of single treatments, the combination of OMF and CDDP resulted in a stronger inhibition of NCI and Mest cell proliferation. OMF combination with CDDP was also able to affect the migratory ability of NCI and Mest cells by down-regulating αv and β5 expression and reducing metalloproteinase 2 (MMP-2) production. In addition, this association was effective in modulating VEGF gene expression. This finding highlights the possibility to use OMF and CDDP together to regulate angiogenesis and tumour progression in mesothelioma. Keywords Mesothelioma . 3-O-methylfunicone . Cisplatin . Integrins . Metalloproteinase . Migration Introduction Malignant pleural mesothelioma (MPM) is a locally invasive and rapidly fatal malignancy linked to asbestos exposure. The frequency of MPM is increasing throughout the world. Surgical resection is possible in a minority of patients, and fewer than 15% of these patients live beyond 5 years [1]. Treatment with radiation therapy is equally disappointing, in part because of difficulties in irradiating disease while avoiding toxicity to normal lung, cardiac and spinal cord tissues. Mesothelioma is particularly resistant to the current therapies and, up to now, the prognosis of most patients is dramatically poor [2]. Recent studies on treatment of mesothelioma with combined chemotherapy demonstrate a survival benefit when a combination of cisplatin and antifolate drugs is used [3]. Cisplatin (cis-platinum(II) diammine dichloride, CDDP) is widely used as a chemotherapeutic agent, displaying clinical activity against a wide variety of tumours. CDDP interacts with DNA to form DNA adducts affecting the double strand, which activate several signal transduction pathways culminating in the activation of apoptosis. E. Buommino : A. De Filippis : A. Rizzo : V. Brancato : M. A. Tufano (*) : G. Donnarumma Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Second University of Naples (SUN), via Luigi de Crecchio n°7, 80128 Naples, Italy e-mail: mariaan.tufano@unina2.it R. Nicoletti Council for Research and Experimentation in Agriculture, CAT Research Unit, Scafati, Italy M. Menegozzo : S. Menegozzo Department of Experimental Medicine, Section of Job Medicine, SUN, Naples, Italy M. L. Ciavatta Institute of Biomolecular Chemistry (ICB-CNR), Pozzuoli, Italy Invest New Drugs (2012) 30:1343–1351 DOI 10.1007/s10637-011-9698-1