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.
Highlights
Angiogenic neovascularisation is central to the pathogenesis and haematogenous dissemination of malignant tumours [1]
MCF-7 human breast cancer and NCI-H460 human non-small cell lung carcinoma cells were treated with a range of concentrations (1 nM - 100 μM) of each antiangiogenic drug for 72 hours, after which cell viability was measured by an MTT assay
When MCF-7 cells were incubated with thalidomide there was a significant concentrationdependent decrease in cell viability at drug concentrations above 1 μM, while NCI-H460 cell viability was only reduced at a thalidomide concentration of 100 μM
Summary
Angiogenic neovascularisation is central to the pathogenesis and haematogenous dissemination of malignant tumours [1]. A plethora of recent evidence has demonstrated that the cancer cells within tumours are significantly more reliant on mitochondrial oxidative metabolism to meet their metabolic energy demands than has been generally assumed since the introduction of the Warburg hypothesis almost 60 years ago [2,3,4,5]. These observations, when taken together, indicate a pivotal role for mitochondria www.impactjournals.com/oncotarget in the pathogenesis of cancer, making them a promising molecular target for anti-cancer therapies. A number of other agents have been identified that act at the mitochondria to cause cancer cell death in vitro, including tricyclic antidepressants such as chlorimipramine [8]; vanilloids such as capsaicin [9]; and cannabinoids such as Δ9-tetrahydrocannabinol (THC), the psychoactive compound in Cannabis sativa [10]
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