We synthesized a mitochondria-targeted honokiol (Mito-HNK) that facilitates its mitochondrial accumulation; this dramatically increases its potency and efficacy against highly metastatic lung cancer lines in vitro, and in orthotopic lung tumor xenografts and brain metastases in vivo. Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation, inhibiting mitochondrial complex ?, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3. Within lung cancer brain metastases in mice, Mito-HNK induced the mediators of cell death and decreased the pathways that support invasion and proliferation. In contrast, in the non-malignant stroma, Mito-HNK suppressed pathways that support metastatic lesions, including those involved in inflammation and angiogenesis. Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers. Its pronounced anti-invasive and anti-metastatic effects in the brain are particularly intriguing given the paucity of treatment options for such patients either alone or in combination with standard chemotherapeutics.

• Klíčová slova
• Immunology, Medicinal and Aromatic Plants, Natural Product Chemistry,
• Publikační typ
• časopisecké články MeSH

Methyltriphenylphosphonium (TPMP) salts have been widely used to measure the mitochondrial membrane potential and the triphenylphosphonium (TPP+) moiety has been attached to many bioactive compounds including antioxidants to target them into mitochondria thanks to their high affinity to accumulate in the mitochondrial matrix. The adverse effects of these compounds on cellular metabolism have been insufficiently studied and are still poorly understood. Micromolar concentrations of TPMP cause a progressive inhibition of cellular respiration in adherent cells without a marked effect on mitochondrial coupling. In permeabilized cells the inhibition was limited to NADH-linked respiration. We found a mixed inhibition of the Krebs cycle enzyme 2-oxoglutarate dehydrogenase complex (OGDHC) with an estimated IC50 3.93 [3.70-4.17] mM, which is pharmacologically plausible since it corresponds to micromolar extracellular concentrations. Increasing the lipophilic character of the used TPP+ compound further potentiates the inhibition of OGDHC activity. This effect of TPMP on the Krebs cycle ought to be taken into account when interpreting observations on cells and mitochondria in the presence of TPP+ derivatives. Compounds based on or similar to TPP+ derivatives may also be used to alter OGDHC activity for experimental or therapeutic purposes.

• MeSH
• buněčné linie MeSH
• citrátový cyklus účinky léků   MeSH
• citrátsynthasa účinky léků   metabolismus   MeSH
• glutamátdehydrogenasa účinky léků   metabolismus   MeSH
• isocitrátdehydrogenasa účinky léků   metabolismus   MeSH
• ketoglutarátdehydrogenasový komplex antagonisté a inhibitory   metabolismus   MeSH
• kosterní svaly enzymologie   MeSH
• krysa rodu Rattus MeSH
• malátdehydrogenasa účinky léků   metabolismus   MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• oniové sloučeniny farmakologie   MeSH
• potkani Wistar MeSH
• pyruvátdehydrogenasový komplex účinky léků   metabolismus   MeSH
• svalové mitochondrie účinky léků   enzymologie   MeSH
• tritylové sloučeniny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• citrátsynthasa MeSH
• glutamátdehydrogenasa MeSH
• isocitrátdehydrogenasa MeSH
• ketoglutarátdehydrogenasový komplex MeSH
• malátdehydrogenasa MeSH
• oniové sloučeniny MeSH
• pyruvátdehydrogenasový komplex MeSH
• triphenylmethylphosphonium MeSH Prohlížeč
• tritylové sloučeniny MeSH

Mitochondrial oxidative damage contributes to a wide range of pathologies. One therapeutic strategy to treat these disorders is targeting antioxidants to mitochondria by conjugation to the lipophilic triphenylphosphonium (TPP) cation. To date only hydrophobic antioxidants have been targeted to mitochondria; however, extending this approach to hydrophilic antioxidants offers new therapeutic and research opportunities. Here we report the development and characterization of MitoC, a mitochondria-targeted version of the hydrophilic antioxidant ascorbate. We show that MitoC can be taken up by mitochondria, despite the polarity and acidity of ascorbate, by using a sufficiently hydrophobic link to the TPP moiety. MitoC reacts with a range of reactive species, and within mitochondria is rapidly recycled back to the active ascorbate moiety by the glutathione and thioredoxin systems. Because of this accumulation and recycling MitoC is an effective antioxidant against mitochondrial lipid peroxidation and also decreases aconitase inactivation by superoxide. These findings show that the incorporation of TPP function can be used to target polar and acidic compounds to mitochondria, opening up the delivery of a wide range of bioactive compounds. Furthermore, MitoC has therapeutic potential as a new mitochondria-targeted antioxidant, and is a useful tool to explore the role(s) of ascorbate within mitochondria.

• Klíčová slova
• Ascorbic acid, Lipid peroxidation, Lipophilic cation, MitoC, MitoPerox, Mitochondria, Mitochondrial targeting,
• MeSH
• antioxidancia chemie   farmakologie   MeSH
• jaterní mitochondrie účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina askorbová chemie   farmakologie   MeSH
• lékové transportní systémy metody   MeSH
• oxidace-redukce MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• kyselina askorbová MeSH