Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative. (15th January 2018)

• Record Type: Journal Article
• Authors: Teixeira, José; Amorim, Ricardo; Santos, Katia; Soares, Pedro; Datta, Sandipan; Cortopassi, Gino A.; Serafim, Teresa L.; Sardão, Vilma A.; Garrido, Jorge; Borges, Fernanda; Oliveira, Paulo J.
• Is Part Of: Toxicology. Volume 393(2018)
• Page Start: 123
• Page End: 139
• Publication Date: 2018-01-15
• Subjects: CsA cyclosporin A -- CV cyclic voltammetry -- DOX doxorubicin -- DPV differential pulse voltammetry -- ETC electron transport chain -- GSH reduced glutathione -- H2O2 hydrogen peroxide -- mPTP mitochondrial permeability transition pore -- OXPHOS oxidative phosphorylation -- RLM rat liver mitochondria -- ROS reactive oxygen species -- SRB sulforhodamine B -- TBARS thiobarbituric acid reactive species -- TMRE tetramethylrhodamine ethyl ester -- TPP triphenylphosphonium -- ΔΨ membrane potential; Menadione -- Mitochondria -- Drug discovery -- Mitochondriotropic menadione derivative -- Doxorubicin; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2017.11.014
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Abstract: Menadione, also known as vitamin K3, is a 2-methyl-1, 4 naphthoquinone with a potent cytotoxic activity mainly resulting from its quinone redox-cycling with production of reactive oxygen species (ROS). Although increased ROS generation is considered a relevant mechanism in cancer cell death, it may not be sufficiently effective to kill cancer cells due to phenotypic adaptations. Therefore, combining ROS-generating agents with other molecules targeting important cancer cell phenotypes can be an effective therapeutic strategy. As mitochondrial dysfunction has been implicated in many human diseases, including cancer, we describe here the discovery of a mitochondrial-directed agent (MitoK3 ), which was developed by conjugating a TPP cation to the C3 position of the menadione's naphthoquinone ring, increasing its selective accumulation in mitochondria, as well as led to alterations of its redox properties and consequent biological outcome. MitoK3 disturbed the mitochondrial bioenergetic apparatus, with subsequent loss of mitochondrial ATP production. The combinatory strategy of MitoK3 with anticancer agent doxorubicin (DOX) resulted in a degree of cytotoxicity higher than those of the individual molecules, as the combination triggered tumour apoptotic cell death evident by caspase 3/9 activities, probably through mitochondrial destabilization or by interference with mitochondrial redox processes. The results of this investigation support the importance of drug discovery process in developing molecules that can be use as adjuvant therapy in patients with specific cancer subtypes.