Effects of the pan-DAC inhibitor LBH589 in estrogen-sensitive and -insensitive breast cancer cells.

Abstract

e13618 Background: The pan-deacetylase inhibitor LBH589 (panobinostat), that is now in phase I-II trials for its antitumor activity in advanced refractory solid tumors and hematologic malignancies, is one of those drugs with both antitumor activity and the ability of modulating the expression of selected molecules involved in different response to therapy. Advanced breast cancer, becoming resistant to conventional treatment, or metastatic disease are potential application of these new approaches. Methods: In the present study, we report the effects of LBH589 in estrogen-sensitive MCF-7 and T47D, and estrogen-insensitive MDA-MB 231 breast cancer cells. Cells were treated with 5-100 nM LBH589 for different periods (untreated cells were used as control). After treatment, we evaluated: 1. cell viability and cytotoxicity with the WST-1 method; 2. apoptosis induction with the Cell Death Detection ELISA PLUS (Roche Applied Science, Germany); 3. cell cycle progression with flow cytometry; 4. estrogen sensitivity gene expression with RT- real time PCR for estrogen receptor (ER), progesterone receptor (PR), and FOXA1. Results: LBH589 caused a significant reduction in cell viability within nanomolar range and the anti-tumour effect was sustained by apoptosis induction and cell cycle arrest in G2/M. The cytotoxic effect was evident in both estrogen-sensitive and insensitive cells. LBH589 at concentrations higher than 50 nM caused also a reduction of ER alpha, PR and FOXA1 expression in MCF7 and T47D cells; no effect was observed in MDA-MB 231 cells where ER alpha, PR and FOXA1 were not detectable before and after treatment. LBH589 is able to smooth down estrogen-sensitivity pathway, almost certainly causing additional modification in cell behavior, that deserves further studies. Conclusions: Our data suggest that LBH589 is a useful compound in the managing of breast cancer due to its potent cytotoxic effect that is detectable in both estrogen-sensitive and insensitive cells (differently by what reported for other DAC-inhibitors). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis