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

BACKGROUND: The lipophilic positively charged moiety of triphenylphosphonium (TPP+) has been used to target a range of biologically active compounds including antioxidants, spin-traps and other probes into mitochondria. The moiety itself, while often considered biologically inert, appears to influence mitochondrial metabolism. METHODOLOGY/PRINCIPAL FINDINGS: We used the Seahorse XF flux analyzer to measure the effect of a range of alkylTPP+ on cellular respiration and further analyzed their effect on mitochondrial membrane potential and the activity of respiratory complexes. We found that the ability of alkylTPP+ to inhibit the respiratory chain and decrease the mitochondrial membrane potential increases with the length of the alkyl chain suggesting that hydrophobicity is an important determinant of toxicity. CONCLUSIONS/SIGNIFICANCE: More hydrophobic TPP+ derivatives can be expected to have a negative impact on mitochondrial membrane potential and respiratory chain activity in addition to the effect of the biologically active moiety attached to them. Using shorter linker chains or adding hydrophilic functional groups may provide a means to decrease this negative effect.

• MeSH
• buněčné linie MeSH
• elektronový transportní řetězec metabolismus   MeSH
• heterocyklické sloučeniny farmakologie   MeSH
• krysa rodu Rattus MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• potkani Wistar MeSH
• spotřeba kyslíku účinky léků   MeSH
• svalové mitochondrie metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• elektronový transportní řetězec MeSH
• heterocyklické sloučeniny MeSH
• organofosforové sloučeniny MeSH
• tris(o-phenylenedioxy)cyclotriphosphazene MeSH Prohlížeč