RESUMEN
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.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias de la Mama Masculina/tratamiento farmacológico , Ácido Gálico/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenosina Trifosfato/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama Masculina/genética , Neoplasias de la Mama Masculina/metabolismo , Neoplasias de la Mama Masculina/patología , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxiciclina/farmacología , Ácido Gálico/análogos & derivados , Masculino , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Biogénesis de Organelos , Fosforilación Oxidativa/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
Mitochondrion is an accepted molecular target in cancer treatment since it exhibits a higher transmembrane potential in cancer cells, making it susceptible to be targeted by lipophilic-delocalized cations of triphenylphosphonium (TPP(+)). Thus, we evaluated five TPP(+)-linked decyl polyhydroxybenzoates as potential cytotoxic agents in several human breast cancer cell lines that differ in estrogen receptor and HER2/neu expression, and in metabolic profile. Results showed that all cell lines tested were sensitive to the cytotoxic action of these compounds. The mechanism underlying the cytotoxicity would be triggered by their weak uncoupling effect on the oxidative phosphorylation system, while having a wider and safer therapeutic range than other uncouplers and a significant lowering in transmembrane potential. Noteworthy, while the TPP(+)-derivatives alone led to almost negligible losses of ATP, when these were added in the presence of an AMP-activated protein kinase inhibitor, the levels of ATP fell greatly. Overall, data presented suggest that decyl polyhydroxybenzoates-TPP(+) and its derivatives warrant future investigation as potential anti-tumor agents.