Send Orders for Reprints to reprints@benthamscience.ae Current Pharmaceutical Design, 2016, 22, 1-11 1 REVIEW ARTICLE 1381-6128/16 $58.00+.00 © 2016 Bentham Science Publishers Determinants of Anti-Cancer Effect of Mitochondrial Electron Transport Chain Inhibitors: Bioenergetic Profile and Metabolic Flexibility of Cancer Cells Félix A. Urra a *, Boris Weiss-López b and Ramiro Araya-Maturana c * a Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile. b Departamento de Química, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. c Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile A R T I C L E H I S T O R Y Received: May 23, 2016 Accepted: July 18, 2016 DOI: 10.2174/138161282266616071 912262 Abstract: Recent evidence highlights that energy requirements of cancer cells vary greatly from normal cells and they exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation (OXPHOS). Interestingly, mitochondrial electron transport chain (ETC) has been identified as an essential component in bioenerget- ics, biosynthesis and redox control during proliferation and metastasis of cancer cells. This dependence converts ETC of cancer cells in a promising target to design small molecules with anti-cancer actions. Several small molecules have been described as ETC inhibitors with different consequences on mitochondrial bioenergetics, viability and proliferation of cancer cells, when the substrate availability is controlled to favor either the glycolytic or OXPHOS pathway. These ETC inhibitors can be grouped as 1) inhibitors of a respiratory complex (e.g. rotenoids, vanilloids, alkaloids, biguanides and polyphenols), 2) inhibitors of several respiratory complexes (e.g. capsaicin, ME-344 and epigallocatechin-3 gallate) and 3) inhibitors of ETC activity (e.g. elesclomol and VLX600). Although pharmacological ETC inhibition may produce cell death and a decrease of proliferation of cancer cells, factors such as degree of inhibition of ETC activity by small molecules, bioenergetic profile and metabolic flexibility of different cancer types or subpopulations of cells in a particular cancer type, can affect the impact of the anti-cancer actions. Particularly interesting are the adap- tive mechanisms induced by ETC inhibition, such as induction of glutamine-dependent reductive carboxylation, which may offer a strategy to sensitize cancer cells to inhibitors of glutamine metabolism. Keywords: Respiratory complexes, oxidative phosphorylation, glutamine metabolism, slow-cycling cancer cells, reductive carboxylation, metabolic remodeling, anti-cancer agents, mitochondrial impairment. INTRODUCTION Although mitochondria have long been known as the producers of energy for the cell, they are also central to cell death, cell differ- entiation, innate immune system, hypoxia sensing, metabolism of calcium and amino acids, iron sulfur center and heme biosynthesis [1]. The locating of bioenergetic control points for cell replication and differentiation inside themselves, in addition to their determi- nant role in cell signaling and apoptotic modes of cell death, con- fers mitochondria an increasing general interest. In cancer cells, mitochondria have an essential role in the acquisition of resistance to apoptosis, maintenance of the high proliferative rate and metasta- sis [1]. Several primary targets for xenobiotic-induced bioenergetics failure in mitochondria are currently recognized [2]. Cancer cells have different metabolic organization than normal cells [3] and different predominant metabolic phenotypes, depend- ing on the type of cancer [4]. Despite, the high glycolysis rate in aerobic conditions described in 1956 (Warburg effect) with reduced or damaged mitochondrial function in cancer cells [5], there are also cancer cells with a high oxidative phenotype, having a func- tional mitochondria [6]. They show dependence on oxidative phos- phorylation (OXPHOS) for the supply of both, ATP and intermedi- ates of tricarboxylic acid (TCA) cycle, necessary for survival and growth [7, 8], opening the possibility to obtain novel anti-cancer compounds targeting the OXPHOS enzyme complexes. *Address correspondence to these authors at Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile; Tel: 56-71-2200285; E-mails: raraya@utalca.cl, felix.urra@qf.uchile.cl Anti-cancer compounds acting on mitochondria have been named mitocans, an acronym derived from mitochondria and can- cer, and are classified according with their molecular mode of ac- tion into [9]: (I) hexokinase inhibitors; (II) mimickers of the Bcl-2 homology-3 (BH3) domain; (III) thiol redox inhibitors; (IV) de- regulators of voltage-dependent anionic channel (VDAC)/adenine nucleotide translocase (ANT) complex; (V) electron transport chain-targeting agents; (VI) lipophilic cations targeting the mito- chondrial inner membrane; (VII) TCA cycle targeting agents; (VIII) mitochondrial DNA (mtDNA)-targeting agents. In this review, we summarize recent evidence on mechanisms of new small molecules described as class V mitocans and discuss the factors participating in their anti-cancer effect. ROLE OF ELECTRON TRANSPORT CHAIN IN CANCER Electron transport chain (ETC) is constituted by four respiratory complexes (Fig. 1A), which are immersed in the mitochondrial inner membrane. ETC activity depends on the availability of NADH and FADH 2 from TCA cycle, which are oxidized by com- plexes I and II, with molecular oxygen being the final acceptor, contributing to the mitochondrial respiration [10]. The energy re- leased in the transfer of electrons is used to pump protons from the matrix into the intermembrane space by complexes I, III and IV, generating a proton-based electrochemical gradient. Dissipation of this gradient through FoF 1 -ATP synthase drives ADP phosphoryla- tion [11]. The coupling between ETC activity and ATP synthesis is known as oxidative phosphorylation (OXPHOS). ETC activity controls the bioenergetics (e.g. ATP synthesis by maintaining the mitochondrial potential membrane [12]), signaling (e.g. production of mitochondrial ROS [13]), biosynthetic pathways (e.g. regenera- tion of NAD + and FAD and TCA cycle function, [14]) and epige- Félix A. Urra