Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

No abstract

The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin--referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of chromatin play an important role in regulating gene expression. Some of the most extensively studied epigenetic modifications involve acetylation/deacetylation of lysines in the tails of the core histones, which is controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs). A controlled balance between histone acetylation and deacetylation appears to be essential for normal cell growth (Waterborg, 2002). Alterations in the structure or expression of HATs and HDACs occur in many cancers (Jones and Baylin, 2002; Marks et al., 2001, 2003; Timmermann et al., 2001; Wang et al., 2001). A structurally diverse group of molecules has been developed that can inhibit HDACs (HDACi) (Arts et al., 2003; Bouchain and Delorme, 2003; Curtin and Glaser, 2003; Johnstone and Licht, 2003; Marks et al., 2003; Remiszewski, 2003; Richon et al., 1998; Yoshida et al., 2003). These inhibitors induce growth arrest, differentiation, and?or apoptosis of cancer cells in vitro and in in vivo tumor-bearing animal models. Clinical trials with several of these agents have shown that certain HDACi have antitumor activity against various cancers at doses that are well tolerated by patients (Gottlicher et al., 2001; Kelly et al., 2002a,b; Piekarz et al., 2001; Wozniak et al., 1999).

Recent evidence indicates that prostaglandins (PGs) possess potent gastric antiulcer properties independent of their known inhibitory effects on acid secretion. The mechanism underlying this cytoprotective property, as it has been called, has remained elusive. Although exogenously administered PGs can prevent disruption of the gastric mucosal barrier, enhance gastric mucosal blood flow, and stimulate mucus and bicarbonate secretion, as well as a number of cellular transport processes, evidence for and against each of these proposed mechanisms for cytoprotection has been demonstrated. Thus, it is doubtful whether any of these effects of PGs on gastric epithelium is the mechanism responsible for cytoprotection, if indeed a single, common mechanism exists. In addition, an association between alterations in endogenous PGs and gastric mucosal injury induced by a variety of damaging agents has also been observed, but the importance of this association in terms of mediating gastric damage needs further clarification. Finally, the phenomenon of adaptive cytoprotection in which mild irritants protect the gastric mucosa against the damaging effects of various necrotizing agents may also be PG mediated since it can be blocked by indomethacin, an inhibitor of PG synthesis, but a clear association between changes in endogenous PGs and adaptive cytoprotection remains to be demonstrated. Despite being inconclusive, these findings suggest that PGs may play a significant role in the pathogenesis of gastric ulceration and may serve an important function in maintaining normal gastric mucosal integrity.

Abstract-Oxidative stress stimulates both growth and apoptosis in cardiac myocytes in vitro. We investigated whether oxidative stress mediates hypertrophy and apoptosis in cyclically stretched ventricular myocytes. Neonatal rat ventricular myocytes cultured on laminin-coated silastic membranes were stretched cyclically (1 Hz) at low (nominal 5%) and high (nominal 25%) amplitudes for 24 hours. Stretch caused a graded increase in superoxide anion production as assessed by superoxide dismutase (SOD)-inhibitable cytochrome c reduction or electron paramagnetic resonance spectroscopy. The role of reactive oxygen species (ROS) was assessed using the cell-permeable SOD/catalase mimetics Mn(II/III)tetrakis(1-methyl-4-peridyl) (MnTMPyP) and EUK-8. Stretch-induced increases in protein synthesis ( 3 Hleucine incorporation) and cellular protein content were completely inhibited by MnTMPyP (0.05 mmol/L) at both low and high amplitudes of stretch. In contrast, while MnTMPyP inhibited basal atrial natriuretic factor (ANF) mRNA expression, the stretch-induced increase in ANF mRNA expression was not inhibited by MnTMPyP. In contrast to hypertrophy, only high-amplitude stretch increased myocyte apoptosis, as reflected by increased DNA fragmentation on gel electrophoresis and an Ϸ3-fold increase in the number of TUNEL-positive myocytes. Similarly, only high-amplitude stretch increased the expression of bax mRNA. Myocyte apoptosis and bax expression stimulated by high-amplitude stretch were inhibited by MnTMPyP. Both low-and high-amplitude stretch caused rapid phosphorylation of ERK1/2, while high-, but not low-, amplitude stretch caused phosphorylation of JNKs. Activation of both ERK1/2 and JNKs was ROS-dependent. Thus, cyclic strain causes an amplitude-related increase in ROS, associated with differential activation of kinases and induction of hypertrophic and apoptotic phenotypes.

Background-There is an increased incidence of heart failure in patients treated concurrently with anthracyclines and the chemotherapeutic anti-erbB2 agent trastuzumab (Herceptin). On the basis of our previous studies with recombinant neuregulin-1␤ (NRG-1␤), a ligand for the erbB2 receptor tyrosine kinase, we hypothesized that activation of erbB2 by anti-erbB2 versus NRG-1 would cause differential effects on myocyte intracellular signaling as well as anthracyclineinduced myofibrillar injury and might potentially account for the clinical toxicity of trastuzumab in the setting of concurrent anthracycline therapy. Methods and Results-We tested this hypothesis using adult rat ventricular myocytes (ARVMs) in culture, assessing myofibrillar structure by immunostaining for myomesin and filamentous actin. Activation of erbB2, extracellular signal-regulated kinase 1/2 (Erk1/2), and Akt was assessed by use of antibodies to phosphorylated activated receptor or kinase detected by immunoblot. ARVMs treated with doxorubicin (0.1 to 0.5 mol/L) showed a concentrationdependent increase in myofilament disarray. NRG-1␤ (10 ng/mL) activated erbB2, Erk1/2, and Akt in ARVMs and significantly reduced anthracycline-induced disarray. In contrast to NRG-1␤, anti-erbB2 (1 g/mL) caused rapid phosphorylation of erbB2 but not Erk1/2 or Akt, with downregulation of erbB2 by 24 hours. Concomitant treatment of myocytes with anti-erbB2 and doxorubicin caused a significant increase in myofibrillar disarray versus doxorubicin alone. Key Words: erbB2 Ⅲ cardiotoxicity Ⅲ neuregulins Ⅲ anthracyclines Ⅲ myocytes T reatment of metastatic breast cancer with anthracyclines and trastuzumab, a novel therapy derived from an antibody to the erbB2 receptor tyrosine kinase, results in a marked increase of left ventricular dysfunction and symptomatic heart failure. 1 ErbB2 is a member of the epidermal growth factor receptor family, and along with neuregulin and the erbB4 receptor, it plays an essential role in cardiac development. [2][3][4] We have shown that recombinant neuregulin 1␤ (NRG-1␤) activates both erbB2 and erbB4 receptor tyrosine kinase activity and promotes growth, myofilament organization, and survival of isolated cardiac myocytes. 5,6 The clinical observation of the cardiotoxicity of trastuzumab and anthracyclines suggests that the neuregulin/erbB system modulates the response of the myocardium to anthracyclines. Possible mechanisms for this toxicity are alterations in the structure, 7 gene expression, 8 and survival 9 of cardiac myocytes. The main purpose of this study was to test the hypothesis that trastuzumab alters the susceptibility of myocytes to anthracycline-induced myofibrillar disarray. We therefore characterized the effect of anthracyclines on myocyte myofibrillar structure in isolated adult rat cardiac myocytes in primary culture and examined the effect of NRG-1␤ and an antibody to erbB2 with properties similar to trastuzumab 10 on erbB2 signaling and anthracycline-induced changes in myofibrillar structure. Conclusions Methods Chemicals...

No abstract

No abstract