O potencial citotóxico, antiproliferativo e anticoagulante de um derivado organometálico do ácido valpróico em uma Linhagem de câncer endometrial

Abstract

Valproic acid (AVP), widely used in the treatment of epilepsy, psychiatric disorders, and migraine, also exhibits antitumor properties mainly associated with the inhibition of histone deacetylases (HDACs), promoting epigenetic modulation and increased cellular sensitivity to cytotoxic agents. However, its prolonged use is associated with significant adverse effects, such as hepatotoxicity and systemic toxicity, which motivates the search for new, safer, and more effective derivative compounds. In this context, organometallic complexes emerge as a promising alternative, notably the derivative [Zn(Valp)₂Phen], which combines valproate with zinc and 1,10-phenanthroline, enhancing interactions with DNA and cytotoxic effects. In parallel, endometrial cancer is a significant public health problem, with a substantial increase in incidence and a need for new therapeutic approaches, especially given the resistance to conventional treatments. Thus, the present study aimed to evaluate the cytotoxic, antiproliferative, and anticoagulant effects of sodium valproate (NaValp) and its derivative [Zn(Valp)₂Phen] on human endometrial tumor cells (Ishikawa), comparing them with endometrial stromal cells (ESCs), and to investigate possible synergism with cisplatin. The results demonstrated that NaValp showed low cytotoxicity, not reaching the IC50 at the tested concentrations, especially in normal cells. In contrast, the organometallic derivative significantly reduced cell viability, with an approximate IC50 of 586 μM (24 h) and 340 μM (72 h) in Ishikawa cells. Furthermore, clonogenic assays confirmed a significant reduction in proliferative capacity, with a decrease of up to 73% in colony formation at higher concentrations of the derivative. Analysis of cell kinetics revealed an increase in population doubling time, indicating a sustained antiproliferative effect. Regarding the interaction with cisplatin, a relevant synergistic effect was observed, especially in the combination of 10 μM cisplatin with 100 μM [Zn(Valp)₂Phen], potentiating cytotoxicity in tumor cells without a significant increase in toxicity in normal cells, suggesting greater therapeutic safety. In relation to anticoagulant activity, NaValp showed a more pronounced effect with prolonged exposure, while the derivative demonstrated a more acute and concentration-dependent action, with a reduction in this effect over time. It is concluded that the organometallic derivative [Zn(Valp)₂Phen] exhibits superior cytotoxic, antiproliferative, and anticoagulant activity compared to sodium valproate, standing out as a potential candidate for the development of new, more selective and effective antitumor therapies. However, further in vitro and in vivo studies are needed for a better understanding of its mechanisms of action and to enable its safe clinical application.