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1.
Cell Chem Biol ; 25(11): 1337-1349.e12, 2018 11 15.
Article in English | MEDLINE | ID: mdl-30122371

ABSTRACT

The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondrial integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Depsipeptides/chemistry , Depsipeptides/pharmacology , Mitochondria/drug effects , Tumor Hypoxia/drug effects , Amino Acid Sequence , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Depsipeptides/therapeutic use , Female , Humans , Male , Mice , Mice, Nude , Mitochondria/metabolism , Mitochondria/pathology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Reactive Oxygen Species/metabolism
2.
Hum Mol Genet ; 22(19): 3819-27, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23727839

ABSTRACT

Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid ß-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment.


Subject(s)
Electron-Transferring Flavoproteins/genetics , Electron-Transferring Flavoproteins/metabolism , Fibroblasts/metabolism , Iron-Sulfur Proteins/genetics , Iron-Sulfur Proteins/metabolism , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/metabolism , Oxidative Stress , Oxidoreductases Acting on CH-NH Group Donors/genetics , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Ubiquinone/analogs & derivatives , Acyl Coenzyme A/metabolism , Ataxia/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Cells, Cultured , Genetic Variation , Humans , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/complications , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/drug therapy , Muscle Weakness/metabolism , Oxidation-Reduction/drug effects , Reactive Oxygen Species/metabolism , Rhodobacter sphaeroides/genetics , Rhodobacter sphaeroides/metabolism , Riboflavin/metabolism , Riboflavin/pharmacology , Ubiquinone/deficiency , Ubiquinone/metabolism , Ubiquinone/pharmacology , Ubiquinone/therapeutic use
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