Reference

The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells

All Rights Reserved. The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Riessland, Markus; Brichta, Lars; Hahnen, Eric; Wirth, Brunhilde ( Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany). Human Genetics, 120(1), 101-110 (English) 2006 Springer. CODEN: HUGEDQ. ISSN: 0340-6717. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the no. of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only ~ 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-b1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs).Several substances like 251456-60-7 may be metioned in this study. Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total no. of gems/nucleus as well as the no. of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of D7-SMN2 into FL-SMN2 transcripts as demonstrated by quant. RT-PCR is most likely facilitated by elevated levels of Htra2-b1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concns. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA. .

Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases

All Rights Reserved. Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. Hoelsken, Annett; Eyuepoglu, Ilker Y.; Lueders, Mike; Traenkle, Christian; Dieckmann, Detlef; Buslei, Rolf; Hahnen, Eric; Bluemcke, Ingmar; Siebzehnruebl, Florian A. (Department of Neuropathology, University of Erlangen-Nuremberg, Erlangen 91054, Germany). Acta Neuropathologica, 112(2), 205-215 (English) 2006 Springer. CODEN: ANPTAL. ISSN: 0001-6322. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Disease progression in patients suffering from malignant melanomas is often detd. by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. 251456-60-7 and 149647-78-9 which are cas registry numbers are also used here. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concns. of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compds. were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21WAF1 were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric anal. Considering the ability of MS-275 to cross the blood-brain barrier, our exptl. model identifies the benzamide MS-275 as a promising therapeutic compd. for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas. .