Combination of pan-histone deacetylase inhibitor and autophagy inhibitor exerts superior efficacy against triple-negative human breast cancer cells
Menée in vitro et in vivo, cette étude évalue l'activité d'un traitement combinant le panobinostat, qui inhibe des histones déacétylases, et la chloroquine, qui inhibe l'autophagie, sur des cellules de cancer du sein triplement négatif
Histone deacetylase (HDAC) inhibitors (HDIs) induce endoplasmic reticulum (ER) stress and apoptosis, while promoting autophagy, which promotes cancer cell survival when apoptosis is compromised. Here, we determined the in vitro and in vivo activity of the combination of the pan-HDI panobinostat (PS) and the autophagy inhibitor chloroquine (CL) against human estrogen/progesterone receptor and HER2 (triple)-negative breast cancer (TNBC) cells. Treatment of MB-231 and SUM159PT cells with PS disrupted the hsp90/histone deacetylase 6/HSF1/p97 complex, resulting in the upregulation of heat shock proteins. This was accompanied by the induction of enhanced autophagic flux as evidence by increased expression of LC3B-II and the degradation of the autophagic substrate p62. Treatment with PS also induced the accumulation and co-localization of p62 with LC3B-II in cytosolic foci as evidenced by immunofluorescent confocal microscopy. Inhibition of PS-induced autophagic flux by CL markedly induced the accumulation of polyubiquitylated proteins and p62, caused synergistic cell death of MB-231 and SUM159PT cells and inhibited mammosphere formation in MB-231 cells, compared to treatment with each agent alone. Finally, in mouse mammary fat pad xenografts of MB-231 cells, a tumor size-dependent induction of heat shock response, ER stress and autophagy was observed. Co-treatment with PS and CL resulted in the reduced tumor burden and increased the survival of MB-231 breast cancer xenografts. Collectively, our findings demonstrate that co-treatment with an autophagy inhibitor and pan-HDI e.g., CL and PS results in accumulation of toxic polyubiquitylated proteins, exerts superior inhibitory effects on TNBC cell growth and increases the survival of TNBC xenografts.
http://mct.aacrjournals.org/content/early/2012/02/24/1535-7163.MCT-11-0979.abstract 2012