title: Liposomal trichostatin A: therapeutic potential in hormone-dependent and -independent breast cancer xenograft models.
abstract: BACKGROUND
  Trichostatin A (TSA) is one of the most potent histone deacetylase inhibitors (HDACi) in vitro but it lacks biological activity in vivo when injected intravenously owing to its fast metabolism.
  
  
  METHODS
  TSA was incorporated into Stealth® liposomes (TSA-lipo) at a high loading and its anticancer activity was evaluated in several types of breast cancer cells and xenografts.
  
  
  RESULTS
  In estrogen receptor α (ERα)-positive MCF-7 and T47-D cells, TSA induced a long-term degradation of cyclin A and a proteasome-dependent loss of ERα and cyclin D1, allowed derepression of p21WAF1/CIP1, HDAC1 and RhoB GTPase, concomitantly with blockade in G2/M of the cell cycle and apoptosis induction. In MDA-MB-231 (MDA) and SKBr-3 cells, TSA increased ERα mRNA and p21WAF1/CIP1 protein expression, but decreased cyclin A with a G2/M blockade and cleavage of polyADP-ribose polymerase (PARP). No significant restoration of any ER protein was noticed in any cells. TSA-lipo markedly inhibited tumor growth in MCF-7 and MDA cells xenografts following intravenous injection. Their anticancer effects were characterized by inhibition of Ki-67 labeling, the inhibition of tumor vasculature and an increase of p21WAF1/CIP1 in both tumors. In MCF-7 cell tumors, enhanced RhoB accumulation in the cytoplasm of epithelial cells was noticed, inversely to ERα that was strongly decreased.
  
  
  CONCLUSIONS
  Such anticancer activity of TSA-lipo is exp-lained by the protection provided by HDACi encapsulation and by the strong tumor accumulation of the nanocarriers as revealed by fluorescence confocal microscopy experi-ments. Together with its lack of toxicity, the enhanced stability of TSA-lipo in vivo justifies its development for therapeutic use in the treatment estradiol-dependent and -independent breast cancers.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Urbinati
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas
authors.forename: Juliette
authors.initials: J
authors.lastname: Vergnaud-Gauduchon
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir