Associação Portuguesa de Investigação em Cancro
Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative
Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative
Authors and Affiliations:
José Teixeira1,2, Ricardo Amorim1, Katia Santos2, Pedro Soares1, Sandipan Datta3, Gino A. Cortopassi3, Teresa L. Serafim2, Vilma A. Sardão2, Jorge Garrido1,4, Fernanda Borges1, Paulo J. Oliveira2
1 CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
2 CNC – Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park – Cantanhede, Portugal
3 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, USA
4 Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic Institute of Porto, Porto, Portugal
Abstract:
Menadione, also known as vitamin K3, is a 2-methyl-1,4 naphthoquinone with a potente 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.
Journal: Toxicology – Elsevier
Link: https://www.sciencedirect.com/science/article/pii/S0300483X1730344X