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

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Bisphenol-A in Drinking Water Accelerates Mammary Cancerogenesis and Favors an Immunosuppressive Tumor Microenvironment in BALB–neuT Mice

“…An additional key mechanism of tumor immune escape is based on the interaction between the immune inhibitory receptor PD-1, expressed on the membrane of T cells, and its ligand PD-L1, expressed on cancer cells and different cell types of the tumor microenvironment [ 57 , 58 ]. Activation of the PD-1/PD-L1 pathway impairs T cell activity, diminishes cytokines production, and prompts immune tolerance towards tumor cells, and the inhibition of this pathway appears as one of the most promising anticancer tools developed recently [ 57 , 95 , 96 , 97 ]. In this study, we show that although PD-L1 was expressed at similar levels in invasive tumors from CTR and BPA-treated mice, its cognate receptor PD-1 was instead significantly increased in the BPA-treated group.…”

“…no. EMP011005, Euroclone, Milan, Italy) as previously described [ 97 ]. Densitometric analysis of autoradiographic bands was performed with Image J software 1.53e (National Institutes of Health, Bethesda, MD, USA) after blot scanning and expressed as bar graphs in the figures.…”

New insights into the Bortezomib‐induced cytotoxic and resistance mechanisms in a primary effusion lymphoma mouse model

“…A better understanding of these mechanisms, as well as of those responsible for the treatment resistance, is important for a more correct use of this drug and to improve the outcome of the treatment. BZ has been shown to mediate a cytotoxic effect against several cancers, either in vitro and in vivo, 4,5 including PEL, that is a lymphoma highly refractory to therapies. 1,3,6 However, regarding the latter, the molecular changes induced by BZ in vivo have been evaluated after only 24 h of treatment.…”