Disruption of the reprogrammed energy management system of malignant cells is a prioritized goal of targeted cancer therapy. Two regulators of this system are the Fer kinase, and its cancer cell specific variant, FerT, both residing in subcellular compartments including the mitochondrial electron transport chain. Here, we show that a newly developed inhibitor of Fer and FerT, E260, selectively evokes metabolic stress in cancer cells by imposing mitochondrial dysfunction and deformation, and onset of energy-consuming autophagy which decreases the cellular ATP level. Notably, Fer was also found to associate with PARP-1 and E260 disrupted this association thereby leading to PARP-1 activation. The cooperative intervention with these metabolic pathways leads to energy crisis and necrotic death in malignant, but not in normal human cells, and to the suppression of tumors growth in vivo. Thus, E260 is a new anti-cancer agent which imposes metabolic stress and cellular death in cancer cells.
Bibliographical noteFunding Information:
This work was supported by grants from the Calb, Luis Sheinman, and Milstein Foundations. We would like to thank Dr Michal Afri, Dr Michal Weitman, Dr Michal Ejgenberg, and Dr Hugo E. Gottlieb from the Chemistry Department at Bar-Ilan university for their kind help with the chemical characterizations of the new entity SMCs described in this article.
© 2017 The Author(s).