Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F17%3A00487179" target="_blank" >RIV/86652036:_____/17:00487179 - isvavai.cz</a>
Výsledek na webu
<a href="http://dx.doi.org/10.1016/j.taap.2017.06.017" target="_blank" >http://dx.doi.org/10.1016/j.taap.2017.06.017</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.taap.2017.06.017" target="_blank" >10.1016/j.taap.2017.06.017</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma
Popis výsledku v původním jazyce
We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondria] uncoupling in vitro due to the increased mitochondrial trans membrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP+ C-8, TPP+C10 and TPP+ C-12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP+ C-10 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+ C-10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP+ C-10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30 days of intraperitoneal (i.p.) administration of the combination of TPP+ C-10 (10 mg/kg/48 h) and the antibiotic doxycycline (10 mg/kg/24 h) completely eliminated the subcutaneous tumor burden in mice (n = 6), without any relapses at 60 days post-treatment. This enhancement of the individual activities of TPP+C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP+ C-10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-ct as an adaptive response. Moreover, i.p. administration of TPP+ C-10 (10 mg/kg/24 h) 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+ C-10 with doxycycline is a valuable candidate therapy for breast cancer management. (C) 2017 Elsevier Inc. All rights reserved.
Název v anglickém jazyce
Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma
Popis výsledku anglicky
We previously demonstrated that alkyl gallates coupled to triphenylphosphine have a selective and efficient antiproliferative effect by inducing mitochondria] uncoupling in vitro due to the increased mitochondrial trans membrane potential of tumor cells. Therefore, in this work, the in vivo antitumor activities of alkyl gallate triphenylphosphonium derivatives (TPP+ C-8, TPP+C10 and TPP+ C-12) were evaluated in a syngeneic murine model of breast cancer. We found that TPP+ C-10 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+ C-10 induced a decrease in the levels of cellular proliferation markers and promoted caspase-3 activation in tumor-bearing mice. Additionally, TPP+ C-10 inhibited tumor growth in the syngeneic mouse model. Importantly, 30 days of intraperitoneal (i.p.) administration of the combination of TPP+ C-10 (10 mg/kg/48 h) and the antibiotic doxycycline (10 mg/kg/24 h) completely eliminated the subcutaneous tumor burden in mice (n = 6), without any relapses at 60 days post-treatment. This enhancement of the individual activities of TPP+C10 and doxycycline is due to the uncoupling of oxidative phosphorylation by TPP+ C-10 and the inhibition of mitochondrial biogenesis by doxycycline, as demonstrated by loss of mitochondrial mass and overexpression of PGC1-ct as an adaptive response. Moreover, i.p. administration of TPP+ C-10 (10 mg/kg/24 h) 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+ C-10 with doxycycline is a valuable candidate therapy for breast cancer management. (C) 2017 Elsevier Inc. All rights reserved.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30104 - Pharmacology and pharmacy
Návaznosti výsledku
Projekt
—
Návaznosti
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2017
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Toxicology and Applied Pharmacology
ISSN
0041-008X
e-ISSN
—
Svazek periodika
329
Číslo periodika v rámci svazku
AUG 15 2017
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
13
Strana od-do
334-346
Kód UT WoS článku
000406735700035
EID výsledku v databázi Scopus
2-s2.0-85021713220