MB standard therapy includes primary tumor resection followed by irradiation and/or chemotherapy.

At the moment, therapy stratification depends on tumor histology, metastasis stage, and patient age. Patients belonging to the high-risk group and such with metastases receive a more intensive concomitant chemoradiotherapy compared to low-risk patients. Infants below 18 months do not obtain radiation therapy to avoid radiation-related adverse late effects, like neurocognitive and psychomotoric deficits, but receive a highly aggressive chemotherapy. With overall 5-year survival rates of approximately 60%, an improved antitumor strategy is urgently needed to further enhance the outcome of the moderate- and high-risk patients (90% of all MB patients). Especially in younger children, a reduction of treatment-induced adverse effects, by applying less toxic agents, is an ambitious aim in MB therapy optimization. Selleckchem Linsitinib Epigenetic aberrations like

HIC1, RASSF1a, or CASP8 promoter methylation, which are observed in most MBs (70–90%), lead to silenced tumor suppressor genes (TSG) and are responsible for the lack of cell cycle arrest and apoptosis in tumor cells [2]. Hence, the application of epigenetic modulators in the treatment of MB might be a suitable approach to improve the standard therapy. Methyltransferase inhibitors like 5-aza-2’-deoxycytidine (5-aza-dC, decitabine) and histone deacetylase inhibitors (HDACi) like valproic acid (VPA) or SAHA are approved for the therapy of other diseases selleck kinase inhibitor such as myelodysplastic syndromes, neurological disorders, or T-cell lymphoma.

Application of epigenetic drugs in leukemia and carcinomas is currently tested in clinical studies. In addition, the low differentiation stage of MB cells constitutes also an attractive approach for MB therapy. The usage of differentiation-inducing drugs may induce neuronal or glial maturation in tumor cells and, therefore, eliminate Sclareol their cancer-causing abilities. For instance, all-trans retinoic acid (ATRA) has already been used in differentiation therapy of leukemia patients. In vitro experiments with abacavir and resveratrol exhibited the drug-mediated induction of a more differentiated cell phenotype in MB cell lines [3–5]. Combination of nucleoside analogs like 5-aza-dC with HDACi might result in amplified effects as HDACi have been shown to suppress the alien nucleotide removal [6]. Also, induction of differentiation might work much more successfully after reactivation of beforehand silenced differentiation-relevant genes [7]. In this study, we tested single and combinatorial effects of 5-aza-dC with other epigenetic drugs (VPA, SAHA) or differentiation inducers (resveratrol, abacavir, ATRA), as detailed below, on the metabolic activity and reproductive survival of human MB cell lines.