We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondrial uncoupling in vitro due to the increased mitochondrial transmembrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP(+)C8, TPP(+)C10 and TPP(+)C12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP(+)C10 increased the cytosolic ADP/ATP ratio and significantly increased the AMP levels in a concentration-dependent manner in TA3/Ha murine mammary adenocarcinoma cells. Interestingly, TPP(+)C10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP(+)C10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30days of intraperitoneal (i.p.) administration of the combination of TPP(+)C10 (10mg/kg/48h) and the antibiotic doxycycline (10mg/kg/24h) completely eliminated the subcutaneous tumor burden in mice (n=6), without any relapses at 60days post-treatment. This enhancement of the individual activities of TPP(+)C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP(+)C10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-α as an adaptive response. Moreover, i.p. administration of TPP(+)C10 (10mg/kg/24h) to healthy mice did not produce toxicity or damage in organs important for drug metabolism and excretion, as indicated by hematological, biochemical and histological assessments. These findings suggest that the combination of TPP(+)C10 with doxycycline is a valuable candidate therapy for breast cancer management.

• MeSH
• adenokarcinom farmakoterapie   genetika   metabolismus   patologie   MeSH
• adenosintrifosfát metabolismus   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• biogeneze organel MeSH
• časové faktory MeSH
• doxycyklin farmakologie   MeSH
• experimentální nádory mléčných žláz farmakoterapie   genetika   metabolismus   patologie   MeSH
• kaspasa 3 metabolismus   MeSH
• kyselina gallová analogy a deriváty   farmakologie   MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prsu u mužů farmakoterapie   genetika   metabolismus   patologie   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• oxidativní fosforylace účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• spotřeba kyslíku účinky léků   MeSH
• tumor burden účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH