title: The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells.
abstract: Cell survival and proliferation are central to carcinogenesis, involving various mechanisms among which those that impede apoptosis are important. In this, the role of the molecular chaperone Hsp60 is unclear since it has been reported that it can be both, pro- or anti-apoptotic. A solution to this riddle is crucial to the development of anti-cancer therapies targeting Hsp60. We addressed this question using a tumor cell line, NCI-H292, and [Cu(3,5-bis(2'-pyridyl)-1,2,4-oxadiazole)2(H2O)2](ClO4)2, CubipyOXA, a copper-containing compound with cytotoxic properties. We treated cells with various doses of the compound and measured cell viability; apoptosis indicators; and levels of Hsp60, pro-Caspase-3 (pC3), Caspase-3 (C3), and complex Hsp60/pC3, with complementary methods. The quantitative dose-response curves of the levels of Hsp60, activated C3, inactivated pC3, Hsp60/pC3 complex and indicators of cell apoptosis, and cell death, all coincided to show that CubipyOXA has pro-apoptotic activity and promotes cell death. The curves also indicate that the pro-apoptotic effects of CubipyOXA could likely be due to a lowering of Hsp60 levels and to its blocking the formation of the Hsp60/pC3 complex and/or its dissociating the complex when already formed, thus, interfering with the anti-apoptotic action of Hsp60. These findings shed some light on how a tumor cell may avert apoptosis using Hsp60 and point to the anti-cancer potential of drugs, such as CubipyOXA, which interfere with Hsp60/pC3 complex formation, and thus allow the apoptotic cascade to proceed. In view of these findings it becomes clear that the novel compound CubipyOXA should be considered a potential, high-efficiency antitumor agent deserving further testing.
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: Caruso Bavisotto
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikolic
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Marino Gammazza
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Barone
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
authors.forename: Filippa
authors.initials: F
authors.lastname: Lo Cascio
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Mocciaro
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zummo
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and IMET, Columbus Center, Baltimore, MD, USA.
authors.forename: Everly
authors.initials: E
authors.lastname: Conway de Macario
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and IMET, Columbus Center, Baltimore, MD, USA.
authors.forename: Alberto Jl
authors.initials: AJ
authors.lastname: Macario
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.affiliation: Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Giacalone
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pace
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Barone
authors.affiliation: Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy. Electronic address: antonio.palumbopiccionello@unipa.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo Piccionello
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy; Euro-Mediterranean Institute of Science and Technology, Palermo, Italy. Electronic address: claudiettacam@hotmail.com.
authors.forename: Claudia
authors.initials: C
authors.lastname: Campanella
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D018834:Chaperonin 60 / Q000378:metabolism*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018834:Chaperonin 60; D056831:Coordination Complexes; C060293:HSPD1 protein, human; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D010069:Oxadiazoles; D003300:Copper; D053148:Caspase 3
keywords: Apoptosis; Cancer; CubipyOXA; Hsp60; Hsp60/pC3 complex; Pro-caspase-3 (pC3)