The Mitochondrion as an Emerging Therapeutic Target in Cancer

Abstract

Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.

Figure 1.. Mitochondrial Therapeutic Targets Undergoing Evaluation in Trials and Their Proposed Mechanism of Action.

This figure is a schematic of a mitochondrion, including a generalized representation of the highlighted therapeutic targets and each of their proposed mechanism of action. The mechanisms of action and selected clinical outcomes are more fully discussed in this review, and selected clinical trials evaluating these therapies are summarized in Table 1 and Table 2. A) CPI-613 inhibits two major mitochondrial enzyme complexes in the TCA cycle, (KGDH) and pyruvate dehydrogenase (PDH).B) DCA (Dichloroacetate) inhibits pyruvate dehydrogenase kinase (PDK), thus activating pyruvate dehydrogenase (PDH) leading to glucose oxidation. C)ME-344 directly targets complex I of OXPHOS. D) Venetoclax is a BH3 mimetic that inhibits BCL2, an anti-apoptotic protein. E) Birinapant, LCL 161, and Debio 1143 are SMAC mimetics which bind to inhibitors of apoptosis which, in turn, enable tumor cell apoptosis. F) ONC201’s mechanism of action is not fully understood, but it has been shown to deplete mitochondrial DNA and disrupt ATP production. G) Minnelide is a water-soluble prodrug of triptolide, a potent heatshock protein (HSP) 70 inhibitor, which releases triptolide into the blood stream to slow tumor growth. H) IACS 10759 is a selective inhibitor of OXPHOS. Abbreviations: BAK BCL2-antagonist/killer, BAX BCL2-associated X protein, BCL2 B-cell lymphoma 2, BH3 Bcl-2 Homology 3, DCA Dichloroacetate, Delta psi m mitochondrial membrane potential, DRP1 Dynamin-related protein 1, KDGH α-ketoglutarate dehydrogenase, mtDNA Mitochondrial DNA, OPA1 Optic atrophy 1, PDH Pyruvate dehydrogenase, SIRT3 Sirtuin-3 mitochondrial NAD-dependent deacetylase, SMAC Second mitochondria-derived activator of caspase, XIAP X-linked inhibitor of apoptosis.