Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma
Original language description
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.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Toxicology and Applied Pharmacology
ISSN
0041-008X
e-ISSN
—
Volume of the periodical
329
Issue of the periodical within the volume
AUG 15 2017
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
334-346
UT code for WoS article
000406735700035
EID of the result in the Scopus database
2-s2.0-85021713220