Alkyl-gallate triphenylphophonium lipophilic cations exhibit anti-proliferative, pro-apoptotic and anti-tumorigenic effects against mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R
Jorge Ferreira
ICBM, Faculty of Medicine, University of Chile, Santiago, RM, Chile
Abstract:
Growing in the absence of growth signals, evading apoptosis, sustaining angiogenesis, developing resistance to chemotherapy, the uncontrolled proliferation, invasion and metastasis characterize cancer cells. Most of cancers are lethal diseases. In a previous study, we showed that alkyl gallates are selectively cytotoxic for mouse mammary adenocarcinoma TA3 cell lines and its multiresistant variant TA3-MTX-R, blocking mitochondrial electron flow, mainly at the NADH-CoQ segment, preventing ATP synthesis. As delocalized lipophilic cations have shown tremendous potential in delivering anticancer agents selectively to tumor cells, here we show the effect of octyl-(C8TPP+) and decyl-gallate triphenylphophonium (C10TPP+) lipophilic cations on TA3 and TA3-MTX-R tumor cell lines and Vero normal cell line. Both compounds selectively brought on cytotoxic effects. C10TPP+ was better than the C8TPP+. IC50 values obtained for C10TPP+ were 0.7 mM (TA3), 0.9 mM (TA3-MTX-R) and 26.7 mM (Vero) after 48 h incubation. Both compounds were performed as oxidative phosphorylation uncouplers and they were able to deplete both mitochondrial transmembrane potential and ATP, and they also released cytochrome c from mitochondria to cytosol. These results suggest that alkyl- gallate triphenylphophonium lipophilic cations induce tumoral cell death through apoptosis as a consequence of the oxidative phosphorylation system inhibition.
Acknowledgements: This work was supported by Grants N° 1090075 from FONDECYT and ACT 112 Anillo Bicentenario.
