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J Inorg Biochem. 2017 May;170:8-16. doi: 10.1016/j.jinorgbio.2017.02.004. Epub 2017 Feb 10.

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.

Author information

1
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.
2
Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
3
Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy "Emerico Luna", University of Palermo, Palermo, Italy.
4
Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore; and IMET, Columbus Center, Baltimore, MD, USA.
5
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.
6
Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
7
Euro-Mediterranean Institute of Science and Technology, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
8
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.
9
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.

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.

KEYWORDS:

Apoptosis; Cancer; CubipyOXA; Hsp60; Hsp60/pC3 complex; Pro-caspase-3 (pC3)

PMID:
28212901
DOI:
10.1016/j.jinorgbio.2017.02.004
[Indexed for MEDLINE]

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