title: Response Profiling Using Shotgun Proteomics Enables Global Metallodrug Mechanisms of Action To Be Established.
abstract: Response profiling using shotgun proteomics for establishing global metallodrug mechanisms of action in two colon carcinoma cell lines, HCT116 and SW480, has been applied and evaluated with the clinically approved arsenic trioxide. Surprisingly, the complete established mechanism of action of arsenic trioxide was observed by protein regulations in SW480, but not HCT116 cells. Comparing the basal protein expression in the two cell lines revealed an 80 % convergence of protein identification, but with significant expression differences, which in turn seem to affect the extent of protein regulation. A clear-cut redox response was observed in SW480 cells upon treatment with arsenic, but hardly in HCT116 cells. Response profiling was then used to investigate four anti-cancer metallodrugs (KP46, KP772, KP1339 and KP1537). Proteome alterations were mapped to selected functional groups, including DNA repair, endocytosis, protection from oxidative stress, protection from endoplasmatic reticulum (ER) stress, cell adhesion and mitochondrial function. The present data suggest that knowledge of the mechanism of action of anti-cancer metallodrugs and improved patient stratification strategies are imperative for the design of clinical studies.
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Dominique
authors.initials: D
authors.lastname: Kreutz
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bileck
authors.affiliation: Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Waehringer Guertel 18-20, 5Q, 1090, Vienna, Austria.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Plessl
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Denise
authors.initials: D
authors.lastname: Wolrab
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.affiliation: Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090, Vienna, Austria.
authors.forename: Bernhard K
authors.identifier: http://orcid.org/0000-0003-0877-1822
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Samuel M
authors.identifier: http://orcid.org/0000-0002-8930-4574
authors.initials: SM
authors.lastname: Meier
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0003-4964-0642
authors.initials: C
authors.lastname: Gerner
keywords: cancer; mechanism of action; metallodrugs; proteomics; response profiling