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首页> 外文期刊>Biochemical Pharmacology >DNA demethylation increases sensitivity of neuroblastoma cells to chemotherapeutic drugs
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DNA demethylation increases sensitivity of neuroblastoma cells to chemotherapeutic drugs

机译：DNA去甲基化可增加神经母细胞瘤细胞对化疗药物的敏感性

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Neuroblastoma is a common embryonal malignancy in which high-stage cases have a poor prognosis, often associated with resistance to chemotherapeutic drugs. DNA methylation alterations are frequent in neuroblastoma and can modulate sensitivity to chemotherapeutic drugs in other cancers, suggesting that manipulation of epigenetic modifications could provide novel treatment strategies for neuroblastoma. We evaluated neuroblastoma cell lines for DNA demethylation induced by 5-Aza-2′-deoxycytidine, using genome-wide and gene-specific assays. Cytotoxic effects of chemotherapeutic agents (cisplatin, doxorubicin and etoposide), with and without 5-Aza-2′-deoxycytidine, were determined by morphological and biochemical apoptosis assays. We observed that the extent of genome-wide DNA demethylation induced by 5-Aza-2′- deoxycytidine varied between cell lines and was associated with expression differences of genes involved in the uptake and metabolism of 5-Aza-2′-deoxycytidine. Treatment of neuroblastoma cells with a combination of chemotherapeutic drugs and 5-Aza-2′-deoxycytidine significantly increased the levels of apoptosis induced by cisplatin, doxorubicin and etoposide, compared to treatment with chemotherapeutic drugs alone. The variable demethylation of cell lines in response to 5-Aza-2′-deoxycytidine suggests that epigenetic modifiers need to be targeted to suitably susceptible tumours for maximum therapeutic benefit. Epigenetic modifiers, such as 5-Aza-2′-deoxycytidine, could be used in combination with chemotherapeutic drugs to enhance their cytotoxicity, providing more effective treatment options for chemoresistant neuroblastomas.
机译：神经母细胞瘤是一种常见的胚胎恶性肿瘤，其中晚期病例预后较差，通常与对化疗药物的耐药性有关。 DNA甲基化改变在神经母细胞瘤中很常见，并且可以调节其他癌症中对化疗药物的敏感性，这表明表观遗传修饰的操纵可以为神经母细胞瘤提供新的治疗策略。我们使用全基因组和基因特异性测定评估了神经母细胞瘤细胞系中由5-Aza-2'-脱氧胞苷诱导的DNA去甲基化。通过形态学和生化细胞凋亡试验确定了有或没有5-Aza-2'-脱氧胞苷的化学治疗药物（顺铂，阿霉素和依托泊苷）的细胞毒性作用。我们观察到5-Aza-2'-脱氧胞苷诱导的全基因组DNA脱甲基程度在细胞系之间变化，并且与参与5-Aza-2'-脱氧胞苷代谢的基因表达差异有关。与单独使用化学治疗药物相比，使用化学治疗药物和5-Aza-2'-脱氧胞苷的组合治疗神经母细胞瘤细胞显着增加了顺铂，阿霉素和依托泊苷诱导的凋亡水平。响应5-Aza-2'-脱氧胞苷的细胞系可变脱甲基化表明，表观遗传修饰剂需要针对适当易感的肿瘤，以获得最大的治疗益处。表观遗传修饰剂（例如5-Aza-2'-脱氧胞苷）可与化学治疗药物联合使用以增强其细胞毒性，为化学耐药性神经母细胞瘤提供更有效的治疗选择。

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