Inhibitory effects of epigenetic modulators and differentiation inducers on human medulloblastoma cell lines

Abstract

BackgroundMedulloblastoma (MB) is the most common malignant brain tumor in childhood with a 5-year survival of approximately 60%. We have recently shown that treatment of human MB cells with 5-aza-2’-deoxycytidine (5-aza-dC) reduces the clonogenic survival significantly. Here, we tested combinatorial effects of 5-aza-dC with other epigenetic (valproic acid, SAHA) and differentiation-inducing drugs (resveratrol, abacavir, retinoic acid) on human MB cells in vitro to intensify the antitumor therapy further.MethodsThree human MB cell lines were treated with 5-aza-dC alone or in combination for three or six days. Metabolic activity was measured by WST-1 assay. To determine long-term reproductive survival, clonogenic assays were performed. Induction of DNA double-strand break (DSB) repair was measured by γH2AX assay.ResultsThe applied single drugs, except for ATRA, reduced the metabolic activity dose-dependently in all MB cell lines. Longer treatment times enhanced the reduction of metabolic activity by 5-aza-dC. Combinatorial treatments showed differential, cell line-dependent responses indicating an important impact of the genetic background. 5-Aza-dC together with resveratrol was found to exert the most significant inhibitory effects on metabolic activity in all cell lines. 5-aza-dC alone reduced the clonogenicity of MB cells significantly and induced DSB with no further changes after adjuvant administration of resveratrol.ConclusionThe observed significant decrease in metabolic activity by combinatorial treatment of MB cells with 5-aza-dC and resveratrol does not translate into long-term reproductive survival deficiency in vitro. Further studies in animal models are needed to clarify the resveratrol-mediated anticancer mechanisms in vivo.

Dose‐dependent short‐ and long‐term effects of ionizing irradiation on neural stem cells in murine hippocampal tissue cultures: neuroprotective potential of resveratrol

“…We have already shown that resveratrol decreases the survival in the most common human medulloblastoma cell lines synergistically with irradiation (manuscript in preparation) and on its own (Patties, Kortmann, & Glasow, ). The resveratrol concentration of 15 μmol/L used in the present study led to a 30% reduction of metabolic activity in medulloblastoma cell lines (Patties et al., ). It should be feasible for a treatment in humans as it is still well below the concentration of 40 μmol/L, which is maximally achievable after intravenous injection (Asensi et al., ).…”

Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing’s sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity

“…For instance, resveratrol has been shown to synergize with paclitaxel (Jazirehi and Bonavida 2004), etoposide (Amiri et al 2013), gemcitabine (Harikumar et al 2010), bortezomib and thalidomide (Bhardwaj et al 2007) and histone deacetylase inhibitors (HDACi) (Yaseen et al 2012). With respect to childhood cancers, it has been demonstrated to cooperate with etoposide, doxorubicin, cytarabine, actinomycin D, methotrexate and paclitaxel (Fulda and Debatin 2004), TRAIL (Fulda and Debatin 2005) and immunotherapy (Soto et al 2011) in neuroblastoma, with decitabine in medulloblastoma (Patties et al 2013) and with vincristine in retinoblastoma (Mahida et al 2013). Only few combination studies have been conducted using synthetic STACs, but those that have done so have reported a synergistic effect of SRT1720 with cisplatin (Shin et al 2014) and bortezomib and dexamethasone (Chauhan et al 2011) and of SRT2183 with HDACi (Scuto et al 2013).…”

“…Resveratrol-but none of the synthetic STACs-has been tested in other childhood cancers, e.g., in acute lymphoblastic leukemia (Dorrie et al 2001;Wieder et al 2001), in neuroblastoma Debatin 2004, 2005;Liontas and Yeger 2004;Nicolini et al 2001;Rigolio et al 2005;Soto et al 2011;van Ginkel et al 2007), in medulloblastoma (Patties et al 2013;Wang et al 2003) and in retinoblastoma (Mahida et al 2013), leading to the conclusion that it has potential as chemotherapeutic agent against pediatric malignancies. Here we show that resveratrol and SRT1720 were effective in ES as well.…”

Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation

“…This has provided the basis for not only a new molecular classification of medulloblastomas, but also the foundation for functional studies in animal models (33,34). An interesting outcome of these high throughput studies is the uncovering of somatic mutations, amplifications and loss of chromatin modifying enzymes, implicating epigenetic perturbations in medulloblastoma genesis (35).…”