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

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.

Growth Inhibition and Apoptotic Effect of Pine Extract and Abietic Acid on MCF-7 Breast Cancer Cells via Alteration of Multiple Gene Expressions Using In Vitro Approach

“…Therefore, there was no need to perform further experiments with them on these cell lines; there was almost no chance for them to be used as therapeutic drugs on these cell lines. Any dose above 100 µM or 0.5 mg/mL is considered within cytotoxic margins, as documented by many studies [ 31 , 32 , 33 , 34 , 35 ] and, consequently, calculation of SI value was not applicable.…”

Chemotherapy resistance and stemness in mitotically quiescent human breast cancer cells identified by fluorescent dye retention

“…These concentrations were established using drug dose–response curves generated using the MTT assay (Supplementary Fig. 2) as previously described [13]. After 72 h, drug-containing medium was removed from cultures and Vybrant ® DiD content analysed cytofluorimetrically.…”

Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment

“…However, careful planning of dosing schedules, duration and route of drug administration may result in more favorable response in patients. Another strategy would be to either combine, less toxic BCL-XL or MCL-1 selective inhibitor with more conventional cytotoxic chemotherapy or treat cells with selective pro-apoptotic agents that directly activate type 2 mitochondrial pathways [84]. Co-targeting BCL-2 and MCL-1 would be another treatment avenue worth exploring for cervical cancer management.…”