Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

• Keywords
• cancer, endothelial cells, fatty acid metabolism, glycolysis, metabolism, nucleotide metabolism, oxidative phoshorylation, tumor micro environment (TME),
• Publication type
• Journal Article MeSH
• Review MeSH

Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.

• Keywords
• ATG4B, biosynthesis, cell death, electron transport chain, endothelial cells, mitochondria, oxidative phosphorylation, oxidative stress, reactive oxygen species,
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Autophagy * MeSH
• Cysteine metabolism   MeSH
• Dextrans metabolism   MeSH
• Respiration MeSH
• Endothelial Cells metabolism   MeSH
• Fibroblasts metabolism   MeSH
• Formaldehyde metabolism   MeSH
• Phosphatidylethanolamines metabolism   MeSH
• Inflammatory Bowel Diseases * metabolism   MeSH
• Isothiocyanates MeSH
• Humans MeSH
• Lipopolysaccharides metabolism   MeSH
• DNA, Mitochondrial metabolism   MeSH
• Mitochondria metabolism   MeSH
• Mechanistic Target of Rapamycin Complex 1 metabolism   MeSH
• Mice MeSH
• AMP-Activated Protein Kinases metabolism   MeSH
• Microtubule-Associated Proteins metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Sirolimus MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Cysteine MeSH
• Dextrans MeSH
• Formaldehyde MeSH
• Phosphatidylethanolamines MeSH
• Isothiocyanates MeSH
• Lipopolysaccharides MeSH
• DNA, Mitochondrial MeSH
• Mechanistic Target of Rapamycin Complex 1 MeSH
• phenethyl isothiocyanate MeSH Browser
• AMP-Activated Protein Kinases MeSH
• Microtubule-Associated Proteins MeSH
• Reactive Oxygen Species MeSH
• Sirolimus MeSH

Increasing evidence points to the respiratory Complex II (CII) as a source and modulator of reactive oxygen species (ROS). Both functional loss of CII as well as its pharmacological inhibition can lead to ROS generation in cells, with a relevant impact on the development of pathophysiological conditions, i.e. cancer and neurodegenerative diseases. While the basic framework of CII involvement in ROS production has been defined, the fine details still await clarification. It is important to resolve these aspects to fully understand the role of CII in pathology and to explore its therapeutic potential in cancer and other diseases.

• Keywords
• OXPHOS, Respiratory complex II, cancer, mitochondria, reactive oxygen species, succinate, succinate dehydrogenase, tricarboxylic acid cycle,
• MeSH
• Molecular Targeted Therapy * MeSH
• Humans MeSH
• Mitochondrial Diseases drug therapy   metabolism   pathology   MeSH
• Mitochondria metabolism   pathology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Electron Transport Complex II metabolism   MeSH
• Electron Transport MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Reactive Oxygen Species MeSH
• Electron Transport Complex II MeSH

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.

• Keywords
• anti-cancer strategy, drug delivery, mitocans, mitochondrial targeting,
• MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Molecular Targeted Therapy MeSH
• Citric Acid Cycle drug effects   MeSH
• Electron Transport Chain Complex Proteins drug effects   metabolism   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Neoplasms drug therapy   metabolism   MeSH
• Oxidation-Reduction drug effects   MeSH
• Disease Progression MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Electron Transport Chain Complex Proteins MeSH
• Antineoplastic Agents MeSH

Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.

• MeSH
• Biguanides pharmacology   MeSH
• Phenformin pharmacology   MeSH
• Glycerolphosphate Dehydrogenase metabolism   MeSH
• Adipose Tissue, Brown cytology   MeSH
• Hypoglycemic Agents pharmacology   MeSH
• Rats MeSH
• Succinic Acid metabolism   MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Metformin pharmacology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Oxidation-Reduction drug effects   MeSH
• Hydrogen Peroxide pharmacology   MeSH
• Rats, Wistar MeSH
• Reactive Oxygen Species metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biguanides MeSH
• Phenformin MeSH
• Glycerolphosphate Dehydrogenase MeSH
• Hypoglycemic Agents MeSH
• Succinic Acid MeSH
• Metformin MeSH
• Hydrogen Peroxide MeSH
• Reactive Oxygen Species MeSH

AIMS: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. RESULTS: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. INNOVATION: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.

• Keywords
• HER2, breast cancer, mitochondria, mitochondrially targeted tamoxifen, respirasome,
• MeSH
• Biomarkers MeSH
• Cell Death drug effects   MeSH
• Cell Respiration drug effects   MeSH
• Molecular Targeted Therapy MeSH
• Electron Transport Chain Complex Proteins antagonists & inhibitors   chemistry   metabolism   MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Membrane Potential, Mitochondrial drug effects   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms drug therapy   metabolism   pathology   MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Receptor, ErbB-2 antagonists & inhibitors   metabolism   MeSH
• Electron Transport Complex I antagonists & inhibitors   chemistry   metabolism   MeSH
• Tamoxifen pharmacology   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• Electron Transport Chain Complex Proteins MeSH
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH
• Receptor, ErbB-2 MeSH
• Electron Transport Complex I MeSH
• Tamoxifen MeSH

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qp site by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qp site inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qp site inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qp site unless intracellular succinate is high. In addition, this validates the Qp site of CII as a target for cell death induction with relevance to cancer therapy.

• MeSH
• Cell Death physiology   MeSH
• Protein Conformation MeSH
• Humans MeSH
• Mitochondria metabolism   physiology   MeSH
• Molecular Sequence Data MeSH
• Mutagenesis, Site-Directed MeSH
• Electron Transport Complex II chemistry   genetics   metabolism   physiology   MeSH
• Amino Acid Sequence MeSH
• Ubiquinone chemistry   genetics   metabolism   MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Electron Transport Complex II MeSH
• respiratory complex II MeSH Browser
• Ubiquinone MeSH

Malignant mesothelioma (MM) is an aggressive type of tumour causing high mortality. One reason for this paradigm may be the existence of a subpopulation of tumour-initiating cells (TICs) that endow MM with drug resistance and recurrence. The objective of this study was to identify and characterise a TIC subpopulation in MM cells, using spheroid cultures, mesospheres, as a model of MM TICs. Mesospheres, typified by the stemness markers CD24, ABCG2 and OCT4, initiated tumours in immunodeficient mice more efficiently than adherent cells. CD24 knock-down cells lost the sphere-forming capacity and featured lower tumorigenicity. Upon serial transplantation, mesospheres were gradually more efficiently tumrigenic with increased level of stem cell markers. We also show that mesospheres feature mitochondrial and metabolic properties similar to those of normal and cancer stem cells. Finally, we show that mesothelioma-initiating cells are highly susceptible to mitochondrially targeted vitamin E succinate. This study documents that mesospheres can be used as a plausible model of mesothelioma-initiating cells and that they can be utilised in the search for efficient agents against MM.

• MeSH
• CD24 Antigen metabolism   MeSH
• Cell Adhesion drug effects   MeSH
• Spheroids, Cellular drug effects   pathology   MeSH
• Phenotype MeSH
• Gene Knockdown Techniques MeSH
• Inhibitory Concentration 50 MeSH
• Neoplasm Invasiveness MeSH
• Humans MeSH
• Mesothelioma, Malignant MeSH
• Mesothelioma metabolism   pathology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Mice, Nude MeSH
• Biomarkers, Tumor metabolism   MeSH
• Cell Line, Tumor MeSH
• Neoplastic Stem Cells drug effects   metabolism   pathology   MeSH
• Lung Neoplasms metabolism   pathology   MeSH
• Disease Progression MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Tocopherols pharmacology   MeSH
• Neoplasm Transplantation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD24 Antigen MeSH
• Biomarkers, Tumor MeSH
• Antineoplastic Agents MeSH
• Tocopherols MeSH