University of Bristol, School of Cellular and Molecular Medicine, Medical Sciences Building, University Walk, Bristol BS8 1TD, UK.
Biochem Pharmacol. 2012 Apr 1;83(7):858-65. doi: 10.1016/j.bcp.2012.01.009. Epub 2012 Jan 18.
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.
神经母细胞瘤是一种常见的胚胎性恶性肿瘤，其中高分期病例预后不良，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化疗药物的敏感性，这表明对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检测评估了 5-Aza-2'-脱氧胞苷诱导的神经母细胞瘤细胞系的 DNA 去甲基化。通过形态学和生化细胞凋亡检测，测定了化疗药物（顺铂、阿霉素和依托泊苷）与 5-Aza-2'-脱氧胞苷联合应用的细胞毒性效应。我们观察到，5-Aza-2'-脱氧胞苷诱导的全基因组 DNA 去甲基化的程度在细胞系之间有所不同，并且与参与 5-Aza-2'-脱氧胞苷摄取和代谢的基因的表达差异有关。与单独使用化疗药物相比，用化疗药物和 5-Aza-2'-脱氧胞苷联合治疗神经母细胞瘤细胞显著增加了顺铂、阿霉素和依托泊苷诱导的细胞凋亡水平。细胞系对 5-Aza-2'-脱氧胞苷的反应性可变去甲基化表明，需要针对适当敏感的肿瘤靶向表观遗传修饰剂，以获得最大的治疗益处。表观遗传修饰剂，如 5-Aza-2'-脱氧胞苷，可以与化疗药物联合使用，以增强其细胞毒性，为耐药性神经母细胞瘤提供更有效的治疗选择。
