Maltonis: a modulator of chromatin structure as potential anti-cancer drug

Hydroxypyrones comprise several classes of molecules characterised by high synthetic versatility and interesting pharmaceutical activities. Recently, with the aim to produce innovative anti-cancer agents, we developed a new class of compounds based on the 3-hydroxy-2-methyl-4-pyrone unit (maltol). In this study, we analysed a previous selected molecule referred to as maltonis, in order to assess its anti-proliferative activity both in vitro and in vivo and to characterize its mechanism of action. We firstly tested in vitro anti-tumour efficacy on a wide panel of human tumour cell lines of different origins, subsequently focusing on hematopoietic cancer cell lines that resulted among the most sensitive to maltonis treatments. Maltonis exposure led to a dose-dependent reduction in cell survival in the leukaemia cell models studied. Sublethal concentrations of maltonis induced profound cell cycle perturbations, particularly affecting G2-M phase, whereas treatments with lethal doses caused the induction of programmed cell death. In order to clarify the mechanism of action, we showed by cell-free assays that maltonis is able to alter the chromatin structure inducing the formation of covalent bonds between genomic DNA and proteins. In addition, we demonstrated the activation of DNA damage response as a consequence of maltonis treatments. Moreover, a microarray-based comparative analysis allowed us to better define the molecular response triggered by maltonis in HL-60 cells, and to identify a peculiar distribution of down-regulated genes related to specific genomic features. Finally, a pilot in vivo experiment on a human AML (HL-60) xenograft murine model demonstrated the tolerability and efficacy of maltonis that allowed to slightly increase mice survival time. Overall, these results show that maltonis exerts its anti-proliferative activity through the induction of complex chromatin structural modifications, thus affecting key cellular processes such as RNA processing and DNA replication.