Derivatives of alkyl gallate triphenylphosphonium exhibit antitumor activity in a syngeneic murine model of mammary adenocarcinoma

Abstract

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.