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.

Materials and 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 p21^WAF1/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 p21^WAF1/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 p21^WAF1/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.

Conclusion: 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.