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Mitochondrial targets | Drugs (phase of development) | Mechanisms of action | Resulting effects on mitochondrial activity | Anticancer effects | Cancer types | Reference |
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CPT1 carnitine O-palmitoyltransferase 1 | Etomoxir (clinical trials) | CPT1 inhibitor: inhibits mitochondrial import of FA | Reduction in FA oxidation and OXPHOS | (i) Reduces viability of leukemia stem cell (ii) Potentiates the effects of chemotherapy | AML | [16] |
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IDH2 mutant | AGI-6780 (clinical trials) | (R140Q) IDH2 mutant inhibitor: reduces TCA flux (reverse and forward) and lipid biosynthesis | Reduction in the accumulation of the oncometabolite, R-2-hydroxyglutarate (2-HG) | Promotion of the differentiation of leukemic blasts | AML | [17] |
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Complex V or FO-F1 ATPase | Oligomycin A (preclinical data) | Inhibitor of the FO subunit | (i) Inhibition of ATP synthesis and reduction of electron flux through the ETC (ii) Induction of ROS and MPTP? | (i) Loss of viability (ii) Inhibits the formation of spheroids | Several tumors including breast cancer | [18] |
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Electron transport chain | Elesclomol (clinical trials) | Inhibitor of the ETC by picking up electrons to the ETC | Inhibition of the electron transport flux and promoting ROS production | Reduction in proliferation and induction of apoptotic cell death | Melanoma including those resistant to BRAF mutant inhibitors |
[5, 19, 20] |
NADH: ubiquinone oxidoreductase or complex I | (i) Rotenone (preclinical data) | (i) CI inhibitor | Decreases OXPHOS and mitochondrial oxidative metabolism | Kills cancer stem cells (50–100 times more potent in mammospheres than in isolated cells) | Breast cancer | [21] |
(ii) Metformin or phenformin (a biguanide related to metformin) (clinical trials) | (ii) Concentrates into mitochondrial matrix and also possesses systemic effects (diabetes drugs) and also AMPK activators. Phenformin is a more potent mitochondrial inhibitor than metformin | Reduction of oxidative phosphorylation and ATP synthesis | (i) Inhibition of cell proliferation and inducing cell death (ii) Decreasing the risk of cancer | Leukemia and several solid tumors | [22, 23] |
Ubiquinol: cytochrome c oxidoreductase or complex III | Phenethyl isothiocyanate (PEITC) | CIII inhibitor | Decreases OXPHOS and induces ROS overproduction | Kills cancer cells | Prostate cancer | [24] |
Pyruvate dehydrogenase kinase | Dichloroacetate (DCA) (clinical trials) | PDK isoenzymes inhibitor increases PDH activity (and reduces glycolytic pathways?) | Increase in pyruvate oxidation, OXPHOS, resulting in ROS overproduction | |
Melanoma, sorafenib resistant hepatocarcinoma, glioblastoma, and other tumors |
[5, 25–27] |
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Glutaminase | (i) 968 (ii) BPTES [bis-2-(5-phenyl-acetamido-1,2,4-thiadiazoyl-2-yl)ethyl sulfide] (preclinical data) (iii) CB-839 (preclinical data and clinical trials) | Inhibit mitochondrial glutaminase and conversion of glutamine in glutamate | Reduce the glutamine metabolism in mitochondria | Block cell growth and invasion | Breast cancer, glioblastoma, and other tumors CB-839 is a selective glutaminase inhibitor currently in phase I clinical trials |
[28–30] |
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Mitochondrial translation | Tigecycline (preclinical) and other mitochondrially targeted antibiotics | Antimicrobial inhibits mitochondrial protein translation | Suppress mitochondrial biogenesis and respiration | Loss of viability | Selectively kill AML stem cells Tumor initiating cells from several cancer cell types | [31] [32] |
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ANT | PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) (clinical trials) | Inactivate ANT by oxidation of Cys residues | Induce MPTP and ROS | Loss of viability | Breast cancer | [33] |
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