title: A Systems Biology Approach to Understanding the Mechanisms of Action of an Alternative Anticancer Compound in Comparison to Cisplatin.
abstract: Many clinically available anticancer compounds are designed to target DNA. This commonality of action often yields overlapping cellular response mechanisms and can thus detract from drug efficacy. New compounds are required to overcome resistance mechanisms that effectively neutralise compounds like cisplatin and those with similar chemical structures. Studies have shown that 56MESS is a novel compound which, unlike cisplatin, does not covalently bind to DNA, but is more toxic to many cell lines and active against cisplatin-resistant cells. Furthermore, a transcriptional study of 56MESS in yeast has implicated iron and copper metabolism as well as the general yeast stress response following challenge with 56MESS. Beyond this, the cytotoxicity of 56MESS remains largely uncharacterised. Here, yeast was used as a model system to facilitate a systems-level comparison between 56MESS and cisplatin. Preliminary experiments indicated that higher concentrations than seen in similar studies be used. Although a DNA interaction with 56MESS had been theorized, this work indicated that an effect on protein synthesis/ degradation was also implicated in the mechanism(s) of action of this novel anticancer compound. In contrast to cisplatin, the different mechanisms of action that are indicated for 56MESS suggest that this compound could overcome cisplatin resistance either as a stand-alone treatment or a synergistic component of therapeutics.
authors.affiliation: Molecular Physiology Department, and the Molecular Medicine Research Group, School of Medicine, University of Western Sydney, Campbelltown, NSW 2751, Australia. e.wright@uws.edu.au.
authors.forename: Elise P
authors.initials: EP
authors.lastname: Wright
authors.affiliation: Proteomics Core Facility, Faculty of Science, University of Technology, Sydney, NSW 2007, Australia. matthew.padula@uts.edu.au.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Padula
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia. v.higgins@unsw.edu.au.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Higgins
authors.affiliation: Molecular Physiology Department, and the Molecular Medicine Research Group, School of Medicine, University of Western Sydney, Campbelltown, NSW 2751, Australia. j.aldrich-wright@uws.edu.au.|School of Science and Health, University of Western Sydney, Campbelltown, NSW 2751, Australia. j.aldrich-wright@uws.edu.au.
authors.forename: Janice R
authors.initials: JR
authors.lastname: Aldrich-Wright
authors.affiliation: Molecular Physiology Department, and the Molecular Medicine Research Group, School of Medicine, University of Western Sydney, Campbelltown, NSW 2751, Australia. j.coorssen@uws.edu.au.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Coorssen
keywords: 2D electrophoresis; platinum; proteomics; yeast