Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDACprotein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 M. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phosphoAkt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation. Histone deacetylase (HDAC)2 is recognized as one of the promising targets for cancer treatment because many HDAC inhibitors have entered clinical trials in both solid and liquid tumors (1-3). Nevertheless, the mechanisms underlying the antiproliferative effects of HDAC inhibitors remain elusive. Although they have been shown to activate the transcription of a defined set of genes through chromatin remodeling (4), increasing evidence suggests that modifications of the epigenetic histone code may not represent the primary cause for HDAC inhibitormediated growth inhibition and apoptosis in cancer cells (5, 6). To date, at least two distinct histone acetylation-independent mechanisms have been described for the action of HDAC inhibitors on cellular targets. First, because certain HDAC members can mediate the deacetylation of non-histone proteins, their inhibition interferes with signaling processes in which these proteins are involved independently of the activity of HDAC inhibitors in transcriptional activation. For example, HDAC3 regulates NFB signaling in the nucleus by deacetylation the Rel-A subunit (7), and HDAC6 modulates microtubule acetylation and chemotactic cell motility by acting as a tubulin dea...
Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptoroverexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27 kip1, and the PDK-1 substrate p70 S6Kwere assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC 50 ϭ 3-4 M), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.Trastuzumab (Herceptin), a humanized monoclonal antibody targeting the extracellular domain of the tyrosine kinase receptor HER2, has been used in combination chemotherapy for the treatment of HER2-overexpressing metastatic breast cancer, an aggressive form of the disease with poor prognosis. More recently, the results of three large adjuvant trials demonstrate that trastuzumab in combination with chemotherapy significantly increased disease-free survival for women with early-stage HER2-positive breast cancer. Despite these advances, the clinical benefit of trastuzumab is compromised by the facts that not all HER2-overexpressing cancers respond clinically to the treatment and that some breast can-
This study is aimed at the pharmacological exploitation of α-tocopheryl succinate (1) to develop potent anti-adhesion agents. Considering the structural cooperativity between the phytyl chain and the carboxylic terminus in determining the anti-adhesion activity, our structural optimization led to compound 5 ([2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-acetic acid), which exhibited an-order-of-magnitude higher potency than 1 in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins (IC 50 , 0.6 μM versus 10 μM). Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis.
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]
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