Kv1.3 inhibitors in the treatment of glioma and melanoma
The groups of Prof.s Szabò and Gulbins demonstrated that the inhibition of the mtKv1.3 by different membrane-permeant specific drugs is able to induce apoptosis in different cancer cell lines in vitro, ex vivo in B-CLL cells and in a in vivo orthotopic mouse melanoma model (Leanza L. et al 2012, Leanza L. et al 2013). Here, I tested different Kv1.3 inhibitors on their ability to influence tumor growth in two types of models, glioma and melanoma. In particular, I investigated whether these drugs are able to induce cell death by depolarizing the mitochondrial membrane, increasing ROS production, eventually leading to cytochrome c release in different cancer cell lines. Thanks to their augmented solubility and mitochondrial targeting ability, the newly synthesized drugs, together with clofazimine, were applied, after a pharmacokinetic analysis, in vivo to a syngeneic glioma model and to the orthotopic melanoma model. Beside the impact on tumor growth, the synergistic effect with ROS level, previously proposed in the in vitro studies, was analyzed. The last part of the study focused on the mechanism of the in vivo action of the precursor and the derivatives in the reduction of melanoma tumor, addressing the influence of these compounds on the immune system. Specifically, an analysis of the response of different immune cell subtypes (macrophages, T and B lymphocytes, regulatory T cells, neutrophils) to Kv1.3 inhibitors was performed.