Anti-angiogenic drugs: direct anti-cancer agents with mitochondrial mechanisms of action

Abstract

// Lewis A. Quayle 1, 2 , Maria G. Pereira 3 , Gerjan Scheper 1 , Tammy Wiltshire 1 , Ria E. Peake 1 , Issam Hussain 1 , Carol A. Rea 1 and Timothy E. Bates 1, 4, 5 1 School of Life Sciences, Joseph Banks Laboratories, University of Lincoln, Lincoln, LN6 7DL, U.K. 2 Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, S10 2RX, U.K. 3 School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Lincoln, LN6 7DL, U.K. 4 Drugs With A Difference Limited, BioCity Nottingham, Nottingham, NG1 1GF, U.K. 5 Marlin Therapeutics Limited, Nottingham Science Park, Nottingham, NG7 2RF, U.K. Correspondence to: Timothy E. Bates, email: admin@drugswithadifference.co.uk Keywords: angiogenesis, chemotherapy, breast cancer, lung cancer, mitochondria Received: October 29, 2016      Accepted: June 17, 2017      Published: September 13, 2017 ABSTRACT Components of the mitochondrial electron transport chain have recently gained much interest as potential therapeutic targets. Since mitochondria are essential for the supply of energy that is required for both angiogenic and tumourigenic activity, targeting the mitochondria represents a promising potential therapeutic approach for treating cancer. Here we investigate the established anti-angiogenesis drugs combretastatin A4, thalidomide, OGT 2115 and tranilast that we hypothesise are able to exert a direct anti-cancer effect in the absence of vasculature by targeting the mitochondria. Drug cytotoxicity was measured using the MTT assay. Mitochondrial function was measured in intact isolated mitochondria using polarography, fluorimetry and enzymatic assays to measure mitochondrial oxygen consumption, membrane potential and complex I–IV activities respectively. Combretastatin A4, OGT 2115 and tranilast were both shown to decrease mitochondrial oxygen consumption. OGT 2115 and tranilast decreased mitochondrial membrane potential and reduced complex I activity while combretastatin A4 and thalidomide did not. OGT 2115 inhibited mitochondrial complex II–III activity while combretastatin A4, thalidomide and tranilast did not. Combretastatin A4, thalidomide and OGT 2115 induced bi-phasic concentration-dependent increases and decreases in mitochondrial complex IV activity while tranilast had no evident effect. These data demonstrate that combretastatin A4, thalidomide, OGT 2115 and tranilast are all mitochondrial modulators. OGT 2115 and tranilast are both mitochondrial inhibitors capable of eliciting concentration-dependent reductions in cell viability by decreasing mitochondrial membrane potential and oxygen consumption.