Approcci innovativi della chemoterapia a base metallica per la cura del mesotelioma pleurico maligno (MPM)

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that originates from mesothelial cells of the pleura, a serous membrane that lines and lubricates the lungs and the inside of the rib cage. The main risk factor for mesothelioma is prolonged exposure to asbestos. Redox stimuli caused by asbestos trigger to a strong and prolonged inflammation, which leads to altered gene expression inducing, inter alia, an increase of antioxidant enzymes and glutathione (GSH), and to the selection of cells characterized by proficient DNA-repair and anti-apoptotic ability. The interplay of all these mechanisms is at the basis of the by intrinsic chemoresistance of MPM. An extensive meta-analysis indicated cisplatin, a platinum(II) complex, as the most effective single agent for MPM treatment, despite an objective response rate of only 23%. The current gold-standard protocols are based on cisplatin combined with the antifolate pemetrexed. However, this chemotherapy regimen improves the median overall survival for patients with MPM of very few months. Furthermore, the tumor recurrence, due to chemoresistance, and the cisplatin heavy side effects limit the therapeutic efficacy. For this reason, we carried out several research lines in order to discover novel metal- based drug candidates. We mainly focused our investigations on platinum(IV) complexes aimed to improve the selectivity, the antitumoral activity, and to bypass the pharmacological resistance to Pt(II)-based drugs, as cisplatin, oxaliplatin and picoplatin. It is widely believed that reduction from Pt(IV) to platinum(II) is essential for the anticancer activity of these complexes, that are otherwise rather inert; therefore, they behave as pro-drugs. Moreover, they could be functionalized with several bioactive molecules (obtained the so-called bi-functional drugs), joining the cytotoxic activity of Pt-based drug with a further biological property. Since MPM arises from a chronic inflammation, the inducible isoform of cyclooxygenase (COX-2) represents a good pharmacological target. Therefore, in a further research line we investigated a cobalt-based complex (called Co-ASS), derived from a well-know COX-2 inhibitor, aspirin. The obtained results showed that the biological activity of the candidate drug mainly depends on the cellular context, as it acts as CO-releasing molecule (CO-RM), which retains a NSAID effect. 2 The second approach aimed to optimize platinum-based combinatorial chemotherapy, in order to reduce cisplatin dosage and therefore, its side effects. Apoptosis resistance in MPM cells is ascribed to the overexpression of proteins activating key pathways, such as c-myc. Thus, we aimed to drop c-myc expression by means of an epigenetic agent, JQ1. We analyzed the pharmacological pattern of the cisplatin-JQ1 association and investigated the better schedule of treatment. Furthermore, in order to have more reliable results , we developed a protocol to perform drug screening on 3D cellular models (spheroids), that more accurately mimic the conditions of the tumor tissue