Universidade de Lisboa, Portugal
Title: Ruthenium-based anti-cancer compounds: Insights into their uptake mechanisms and cellular targets
Fernanda Marques is graduated in Chemical Engineering from Instituto Superior Técnico, Universidade de Lisboa and has a PhD in Biochemistry from Faculdade de Ciências, Universidade de Lisboa. She is a Scientifi c Researcher at Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, a Nuclear Tecnological Institute for Research. During the last ten years, she has been involved in the biological evaluation of (radio)metal-based compounds as potential therapeutic agents. She has published more than 50 papers in reputed journals.
Ruthenium compounds have shown highly promising anticancer activity and may provide a less toxic and more eff ective alternatives to platinum-based chemotherapies. Many diff erent ruthenium compounds have been tested for their anticancer properties, however without enough investigation into their mode of action. With the aim to give a contribution to elucidate their mechanism of action we studied a set of structurally related Ru(5-C5H5) complexes with bidentate N,N´-heteroaromatic ligands as prospective metallodrugs, with focus on exploring the uptake, cell death mechanisms and potential cellular targets. Th ese complexes enter the cells by a temperature-dependent process, probably facilitated by binding to plasma transferrin, present high anti proliferative effi cacy in a broad range of tumor cells, preferential localization at the cell membrane and cytosol and the ability to inhibit a lysosomal enzyme, acid phosphatase, in a dose-dependent mode. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. Th e reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Th e results from this study indicated that these ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complexes. In vivo antitumor activity of these complexes in a prostate tumor animal model is underway.