The antitumor effects of OSU-HDAC42, a novel histone deacetylase inhibitor, in HER-2-positive breast cancer

Abstract

e14587 Background: Elevated HER-2/neu expression in primary breast tumors is associated with frequent relapse and poor prognosis. For this reason, HER-2/neu has been actively pursued as a target for novel therapeutic agents. Histone deacetylase inhibitors (HDACi), a new class of antitumor drugs, can downregulate HER2 through hyperacetylation of heat shock protein 90 (hsp90), an important ATP-dependent chaperone that mediates the stability and maturation of a variety of important oncogenic proteins, including HER2, Akt and ERα. In this study, we assess the effects of OSU-HDAC42, a novel orally bioavailable phenylbutyrate-based HDAC inhibitor, on hsp90 and HER2 downregulation. Methods: OSU-HDAC42 was tested for effects on the human breast cancer cell lines BT474, SKBR3, MDA-MB-231 and MCF-7. Assays of cell viability, cell cycle, apoptosis, HER2 expression, phosphorylation, and hsp90 acetylation were performed. Tumor growth was assessed in an orthotopic HER2+ mammary tumor model, using diets ± OSU-HDAC42. Results: SKBR3 (HER2+, ERα-) was the most susceptible to the antiproliferative effects of OSU-HDAC42 after 72 hours of treatment (IC50 = 0.025 μmol/L), followed by BT474 (HER2+, ERα+), MCF-7 (HER2-, ERα+) and MDA-MB-231 (HER2-, ERα-) cells with IC50 values calculated at 0.16, 0.19 and 0.2 μmol/L, respectively, which correlated with the level of inhibition of Hsp90 client protein expression (HER2, Akt). OSU-HDAC42 yields 43- or 65- fold greater cell killing than suberoylanilide hydroxamic acid (SAHA; vorinostat) or MS-275, respectively, and more potently suppresses the levels of Hsp90 client proteins (HER2, ERα and Akt) and induction of apoptosis in HER2+ breast cancer cells. In vivo administration of OSU-HDAC42 resulted in reductions of 76% and 82% in NT5 (HER2+,ER-) tumor mass and volume, respectively, concomitant with tubulin hyperacetylation, increased PARP cleavage, and decreased HER2 levels in OSU-HDAC42 treated mouse tumors. Conclusions: OSU-HDAC42 is a potent inhibitor of HER2+ breast cancer, mediated in part through hsp90 downregulation. As an orally bioavailable HDAC inhibitor with greater potency than other clinically available HDACi agents, OSU- HDAC42 warrants evaluation in clinical trials as a novel therapy for HER2+ breast cancer. [Table: see text]