Antiproliferative effect of ferrocifen drug candidates on malignant pleural mesothelioma cell lines

The purpose of this study was to investigate the antiproliferative potential of two novel bio-organometallic drug candidates, based on hydroxyl-phenyl-but-1-ene skeleton and containing the ferrocenyl (Fc) moiety, namely ferrociphenol (Fc-diOH) and ferrocifen (Fc-OH-TAM), on two cell lines, named BR95 (epithelial-like) and MM98 (sarcomatous-like), obtained from pleural effusions of previously untreated malignant pleural mesothelioma (MPM) patients. In vitro chemosensitivity of MPM cells towards the title compounds was evaluated by cell viability assay, alkaline Single Cell Gel Electrophoresis (Comet test) and western blotting evaluation of p53 induction. The two bio-organometallic derivatives were found to be more potent in inhibiting cell proliferation than the reference metallo-drug cisplatin (CDDP). This antiproliferative effect cannot be attributed to estrogenic/antiestrogenic activity, since both cell lines resulted to be estrogen insensitive (ER−). Fc-diOH and CDDP were able to upregulate wild type p53 present in MM98 cell line, while Fc-OH-TAM was not. Similarly, Fc-diOH and CDDP induced early DNA damage, while Fc-OH-TAM did not. This indicates that, albeit the similar structures, the two ferrocifens exhert different mechanisms of cytotoxicity on MPM cells.

Graphical abstractProposed intracellular activation of Fc-diOH giving rise to alkylating quinine methide. This complex pathway corresponds to intracellular oxidation of ferrocenyl moiety, followed by removal of a phenolic proton, leading to the formation of a quinone methide, an electrophilic species able to react with macromolecules, especially DNA leading to genotoxic effects.Figure optionsDownload full-size imageDownload as PowerPoint slide