In vitro inhibition of human mesothelioma cells by paclitaxel-releasing mesenchymal stromal cells

OBJECTIVE: Malignant pleural mesothelioma (MPM) is a rare fatal asbestos-related malignancy originating in the mesothelial cells of the pleura. A platinum-based doublet containing a third-generation antifolate is the front-line standard of care whilst there are no approved second-line treatments for MPM which remains a disease setting to test the efficacy of new therapeutic agents. Recent studies have demonstrated that mesenchymal stromal cells (MSCs) are able to migrate specifically to tumors and their metastatic sites when administered intravenously. Our group previously demonstrated that PTX-primed MSCs provide a new approach for cancer therapy. It also has been reported that a patient with MPM not responsive to standard first-line treatment, had good response after treatment with nanoparticle albumin-bound paclitaxel and carboplatin, suggesting that new delivery strategies might improve the clinical management of this disease. Aim of this study was to evaluate the in vitro antiproliferative effect of PTX-releasing MSCs on human MPM. MATERIALS AND METHODS: Bone marrow mesenchymal stromal cells (BM-MSCs) were loaded with pemetrexed (PMX) and paclitaxel (PTX) according to a standardized procedure. The primed cells (BM-MSCs/PMX and BM-MSCs/PTX) were lysed and tested in vitro by a 7 days antiproliferation MTT assay against NCI-H28 mesothelioma and a panel of tumor cell lines: T98G (glioblastoma multiforme), U87MG (likely glioblastoma), UPCI-SCC-154 (squamous oral carcinoma) and MOLT-4 (acute lymphoblastic leukemia). RESULTS: The in vitro anticancer activity of pure PTX was significantly higher than that of PMX against all the cell lines tested; in particular, on NCI-H28, the activity of PTX was 14.7 times higher than that of PMX. No inhibitory activity was exerted by the lysate of BM-MSCs loaded with PMX (BM-MSCs/PMX), whereas a significant antitumor activity was produced by the lysate from PTX-loaded BM-MSCs (BM-MSCs/ PTX). Based on these data, we calculated that a single drug loaded BM-MSCs cell can delivery about 0.15 pg of PTX. By homing 106 BM-MSC/PTX into 1 cm3 of tumor mass, we can estimate a PTX delivery near to the concentration of 150 ng/ml corresponding to a value 26 times higher than IC50. CONCLUSION: These preliminary results demonstrated the good activity of PTX against a mesothelioma cell line growth in vitro. Furthermore, also PTX-loaded mesenchymal stromal cells can successfully inhibit the in vitro proliferation of human mesothelioma cells. Further studies and in vivo testing are required to confirm these data that could open the way to improve the mesothelioma therapy by apply a cell mediated system for drug delivery