Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

Table 1

Examples of potential mitochondrial targets for cancer treatment.

Mitochondrial targets	Drugs; (phase of development)	Mechanisms of action	Resulting effects on mitochondrial activity	Anticancer effects	Cancer types	Reference
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]
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]
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]
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]
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]
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]
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]