Juan Yuan1, Núria Llamas Luceño1, Bjoern Sander2, Monika M Golas3,4. 1. Department of Biomedicine, Aarhus University, Wilhelm-Meyers-Alle 3, 8000, Aarhus C, Denmark. 2. Center for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Wilhelm-Meyers-Alle 3, 8000, Aarhus C, Denmark. 3. Department of Biomedicine, Aarhus University, Wilhelm-Meyers-Alle 3, 8000, Aarhus C, Denmark. mgolas@biomed.au.dk. 4. Department of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. mgolas@biomed.au.dk.
Abstract
PURPOSE: Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastoma patients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastoma patients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain. METHODS: Protein levels of histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) in medulloblastoma-derived cells (Daoy and D283 Med), as well as in developing and differentiated brain cells, were determined and compared. Class I and II histone deacetylase inhibitors (HDACi) and a DNMT inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), were applied to Daoy and D283 Med cells, and their effects were studied using viability, apoptosis and cancer sphere assays. RESULTS: We found that in HDAC1 and DNMT1 overexpressing medulloblastoma-derived cells, cell death was induced under various epigenetic drug conditions tested. At low HDACi concentrations, however, a pro-proliferative effect was observed. Parthenolide, a drug that affects cancer stem cells, was found to be efficient in inducing cell death in both cell lines tested. In contrast, we found that Daoy cells were more resistant to 5-aza-dC than D283 Med cells. When suberoylanilide hydroxamic acid (SAHA) and parthenolide were individually applied to both cell lines in combination with 5-aza-dC, a synergistic effect on cell survival was observed. CONCLUSIONS: Our current results suggest that the application of HDACi in combination with drugs that target DNMT may represent a promising option for the treatment of medulloblastoma.
PURPOSE:Medulloblastomas are aggressive brain malignancies. While considerable progress has been made in the treatment of medulloblastomapatients with respect to overall survival, these patients are still at risk of developing neurologic and cognitive deficits as a result of anti-cancer therapies. It is hypothesized that targeted molecular therapies represent a better treatment option for medulloblastomapatients. Therefore, the aim of the present study was to test a panel of epigenetic drugs for their effect on medulloblastoma cells under mild hypoxic conditions that reflect the physiological concentrations of oxygen in the brain. METHODS: Protein levels of histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) in medulloblastoma-derived cells (Daoy and D283 Med), as well as in developing and differentiated brain cells, were determined and compared. Class I and II histone deacetylase inhibitors (HDACi) and a DNMT inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC), were applied to Daoy and D283 Med cells, and their effects were studied using viability, apoptosis and cancer sphere assays. RESULTS: We found that in HDAC1 and DNMT1 overexpressing medulloblastoma-derived cells, cell death was induced under various epigenetic drug conditions tested. At low HDACi concentrations, however, a pro-proliferative effect was observed. Parthenolide, a drug that affects cancer stem cells, was found to be efficient in inducing cell death in both cell lines tested. In contrast, we found that Daoy cells were more resistant to 5-aza-dC than D283 Med cells. When suberoylanilide hydroxamic acid (SAHA) and parthenolide were individually applied to both cell lines in combination with 5-aza-dC, a synergistic effect on cell survival was observed. CONCLUSIONS: Our current results suggest that the application of HDACi in combination with drugs that target DNMT may represent a promising option for the treatment of medulloblastoma.
Entities:
Keywords:
5-aza-2’-deoxycytidine; Cancer stem cells; HDAC inhibitor; Medulloblastoma; Parthenolide; SAHA
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