Discoveries made over the last decade have shown that critical changes in cancer cells, such as activation of oncogenes and silencing of tumor suppressor genes are caused not only by genetic but also by epigenetic mechanisms. While epigenetic alterations are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them perfect targets for therapeutic intervention. Covalent modi cations of chromatin, such as methylation of DNA and acetylation and methylation of histones, are important components of epigenetic machinery. Multiple recent studies have shown that epigenetic modi ers are candidates for potent new drugs in multiple cancers' therapies, including gliomas, and several clinical trials are ongoing. However, as with other chemotherapeutic drugs, toxicity is one of the main concerns with some of the potent epigenetic drugs. Synergistic combinations of these agents are one approach to overcoming toxicity issues while enhancing e cacy. In this study we demonstrated that while individually BIX01294, an inhibitor of histone methyltransferase G9a, DZNep, an inhibitor of lysine methyltransferase EZH2, and Trichostatin A (TSA), an inhibitor of histone deacetylase at their low concentrations showed a moderate effect on the viability of U87 glioblastoma cells, in combinations they exhibited a synergistic effect. Importantly, these combinations exhibited minimal effect on adipose mesenchymal stem cells (AD-MSCs) growth. Thus, unique combinations and concentrations of epigenetic modi ers, that synergistically attenuated the U87 glioblastoma cells while exhibiting minor or moderate effects on normal stem cell growth, have been discovered.
Infants born prematurely have immature lungs, and the neural mechanisms that control breathing are still developing. Premature infants often require supplemental oxygen therapy (hyperoxia) which acutely improves oxygen saturation but consequently leads to bronchopulmonary dysplasia (BPD; chronic lung disease in infants). Whether hyperoxia‐induced BPD also exacerbates the control of breathing is unknown. Thus, the major objective of this study was to elucidate the short and long‐term effects of hyperoxia‐induced BPD on the control of breathing. Sprague Dawley rat pups were exposed to room air (21% O2/Bal. N2) or hyperoxia (90% O2/Bal. N2) from postnatal day 0–10 (P0–10) and ventilation measured during room air (20 min) and hypoxic (10 min; 12% O2/Bal. N2) conditions at P10, 12, 14, 17, 21, 43, and 60 using plethysmography to test the hypothesis that hyperoxia‐induced BPD would decrease breathing stability and impair development of key brainstem respiratory nuclei. By P20, hyperoxic treated pups had significantly (p<0.05) reduced inspiratory (33%) and expiratory flow rates (24%) compared to control (normoxic‐reared) pups, consistent with BPD and pulmonary histologic data from prior publications. Minute ventilation in hyperoxia‐treated pups was significantly decreased (−20% of control) at P10 but increased thereafter while breathing room air (+50% of control; P12–14), and increased ~25% under hypoxic conditions (P12–14, 60, p<0.05). These changes were initially driven by significant increases in breathing frequency (P12–17; +20–46%) and later by increased tidal volume (P43–60; 50%). Room air and hypoxia breathing frequency variability was significantly lower by 20–35% from P10–21 and elevated by 70% at P60, respectively. Moreover, the cumulative histograms of breathing frequencies binned every 10 breaths/min were significantly different in room air and hypoxia conditions across all ages in hyperoxic pups compared to control pups. Preliminary analyses indicated tidal volume variability across room air and hypoxia is also significantly elevated acutely (P10) by 100% and chronically (P60) by 250% in hyperoxic pups compared to control pups. Additional preliminary data indicate increased expression of an astrocytic marker (GFAP) throughout brainstem respiratory nuclei in P60 rats perinatally treated with hyperoxia, consistent with astrogliosis. These data demonstrate significant and lasting anatomical and physiological changes to the brainstem and the neural control of breathing in a rat model of BPD, suggesting additional potential pathologies in human BPD patients.Support or Funding InformationChildren's Hospital of Wisconsin Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Discoveries made over the last decade have shown that critical changes in cancer cells, such as activation of oncogenes and silencing of tumor suppressor genes are caused not only by genetic but also by epigenetic mechanisms. While epigenetic alterations are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them perfect targets for therapeutic intervention. Covalent modifications of chromatin, such as methylation of DNA and acetylation and methylation of histones, are important components of epigenetic machinery. Multiple recent studies have shown that epigenetic modifiers are candidates for potent new drugs in multiple cancers’ therapies, including gliomas, and several clinical trials are ongoing. However, as with other chemotherapeutic drugs, toxicity is one of the main concerns with some of the potent epigenetic drugs. Synergistic combinations of these agents are one approach to overcoming toxicity issues while enhancing efficacy. In this study we demonstrated that while individually BIX01294, an inhibitor of histone methyltransferase G9a, DZNep, an inhibitor of lysine methyltransferase EZH2, and Trichostatin A (TSA), an inhibitor of histone deacetylase at their low concentrations showed a moderate effect on the viability of U87 glioblastoma cells, in combinations they exhibited a synergistic effect. Importantly, these combinations exhibited minimal effect on adipose mesenchymal stem cells (AD-MSCs) growth. Thus, unique combinations and concentrations of epigenetic modifiers, that synergistically attenuated the U87 glioblastoma cells while exhibiting minor or moderate effects on normal stem cell growth, have been discovered.
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