Kinesin Eg5 Selective Inhibition by Newly Synthesized Molecules as an Alternative Approach to Counteract Breast Cancer Progression: An In Vitro Study

SIMPLE SUMMARY: Breast cancer is the most widespread and diagnosed cancer in women. This study tested newly synthesized Eg5 inhibitors to find valid therapeutic alternatives to common drugs able to counteract breast cancer progression. Our results evidence that thiadiazole-based Eg5 inhibitors, 2 and 41, appear to negatively modulate proliferation, invasiveness and migration of cancer cells, affecting also the angiogenesis process and the remodeling of the extracellular matrix, thus representing a new promising drug strategy to control breast cancer. ABSTRACT: Breast cancer (BC) is one of the most diagnosed cancers in women. Recently, a promising target for BC treatment was found in kinesin Eg5, a mitotic motor protein that allows bipolar spindle formation and cell replication. Thus, the aim of this work was to evaluate the effects of novel thiadiazoline-based Eg5 inhibitors, analogs of K858, in an in vitro model of BC (MCF7 cell line). Compounds 2 and 41 were selected for their better profile as they reduce MCF7 viability at lower concentrations and with minimal effect on non-tumoral cells with respect to K858. Compounds 2 and 41 counteract MCF7 migration by negatively modulating the NF-kB/MMP-9 pathway. The expression of HIF-1α and VEGF appeared also reduced by 2 and 41 administration, thus preventing the recruitment of the molecular cascade involved in angiogenesis promotion. In addition, 2 provokes an increased caspase-3 activation thus triggering the MCF7 apoptotic event, while 41 and K858 seem to induce the necrosis axis, as disclosed by the increased expression of PARP. These results allow us to argue that 2 and 41 are able to simultaneously intervene on pivotal molecular signaling involved in breast cancer progression, leading to the assumption that Eg5 inhibition can represent a valid approach to counteract BC progression.