Molecular properties and antiproliferative activity against tumor cells of a new poly-alkylamino-bis-maltolic synthetic molecule (maltonis)

Introduction Hydroxypyrones are highly versatile molecules and several members of this family, both alone and in combination with metals, were found to exert anti-proliferative activities against a wide range of tumor cells. In this study, we show the anti-tumor potential of the prototype of new molecules belonging to the family of hydroxypyrones, named maltonis [4(N),10(N)-bis[(3- hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane], in different tumor cell lines (derived from both hematopoietic and solid human tumors). Methods and Results We examined the potential of maltonis to induce, in cell-free assays, covalent modifications of DNA structure, together with anticancer activities (cell growth inhibition, cell cycle perturbations, effects on programmed cell death). The cellular response to maltonis treatment was assessed also at the molecular level by evaluation of the transcript level of genes involved in cell cycle and programmed cell death regulation. The possible induction of a maltonis-mediated DNA damage response was investigated monitoring the histone H2AX phosphorylation ({gamma}H2AX). Sarcoma cell lines appeared to be particularly sensitive to maltonis in in vitro assays. Consistently, preliminary in vivo experiments reported a cytostatic effect of maltonis, monitoring a consistent reduction of the neoplastic lesions, when intra-tumor injected at doses of 20/40 mg/kg (for two weeks) in a xenograft model of Ewing Sarcoma. However, a range of different levels of sensitivity was observed in the different histotypes (osteosarcoma, Ewing sarcoma and rhabdomyosarcoma) and among cell lines, indicating the need of further studies to identify markers of efficacy. Conclusions Taken together, these results show that maltonis appears to be a good candidate for sarcoma treatment. It induces complex DNA structural modifications, which need to be further analysed in order to clarify mechanisms of action and efficacy of this new drug.