A multi-action Pt(IV) prodrug against aggressive cancer cells

Glioblastoma and malignant mesothelioma are highly aggressive tumors characterized by therapeutic resistance and poor prognosis. To address these challenges, the Pt(IV) prodrug, Pt(IV)Ac-POA, where cisplatin is linked to the histone deacetylase inhibitor (HDACi) 2-(2-propynyl)octanoic acid (POA), was investigated. The compound takes advantage of its lipophilicity which enhances cell uptake, while the HDACi promotes chromatin decondensation, increasing DNA sensitivity to platination. Following preliminary studies on multiple cell models, the effects on human glioblastoma and human biphasic mesothelioma were investigated. Results demonstrated that Pt(IV)Ac-POA triggers various regulated cell death pathways, such as apoptosis, autophagy, necroptosis, and ferroptosis, often outperforming standard cisplatin. Moreover, the compound suppressed DNA repair mechanisms. Studies on glioblastoma cells also revealed the advantages of combining chemotherapy with mycotherapy and, above all, with hadrontherapy (carbon ion radiotherapy). This integrated protocol further reduced clonogenicity and amplified long-term antitumor effects compared to single-agent treatments, thus representing a promising strategy to improve therapeutic outcomes.