Antitumoral effects of Bortezomib in malignant mesothelioma: evidence of mild endoplasmic reticulum stress in vitro and activation of T cell response in vivo

Monica Benvenuto, Valentina Angiolini, Chiara Focaccetti, Daniela Nardozi, Camilla Palumbo, Raffaele Carrano, Alessandra Rufini, Riccardo Bei, Martino Tony Miele, Patrizia Mancini, Giovanni Barillari, Mara Cirone, Elisabetta Ferretti, Grazia Raffaella Tundo, Luciano Mutti, Laura Masuelli, Roberto Bei

Malignant mesothelioma (MM) is a rare tumor with a dismal prognosis. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients' survival. Bortezomib (Bor) is a specific and reversible inhibitor of the chymotrypsin-like activity of the 20S core of the proteasome, currently approved for the treatment of multiple myeloma and mantle cell lymphoma. On the other hand, Bor appears to have limited clinical effects on solid tumors, because of its low penetration and accumulation into tumor tissues following intravenous administration. These limitations could be overcome in MM through intracavitary delivery, with the advantage of increasing local drug concentration and decreasing systemic toxicity. In this study, we investigated the effects of Bor on cell survival, cell cycle distribution and modulation of apoptotic and pro-survival pathways in human MM cell lines of different histotypes cultured in vitro. Further, using a mouse MM cell line that reproducibly forms ascites when intraperitoneally injected in syngeneic C57BL/6 mice, we investigated the effects of intraperitoneal Bor administration in vivo on both tumor growth and the modulation of the tumor immune microenvironment. We demonstrate that Bor inhibited MM cell growth and induced apoptosis. Further, Bor activated the Unfolded Protein Response, which however appeared to participate in lowering cells' sensitivity to the drug's cytotoxic effects. Bor also affected the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors, including ERK1/2 and AKT. In vivo, Bor was able to suppress MM growth and extend mice survival. The Bor-mediated delay of tumor progression was sustained by increased activation of T lymphocytes recruited to the tumor microenvironment. The results presented herein support the use of Bor in MM and advocate future studies aimed at defining the therapeutic potential of Bor and Bor-based combination regimens for this treatment-resistant, aggressive tumor.