依硫磷酸增强G2/M期细胞周期特异性化疗药物抗肿瘤作用的生物信息学预测及其分子机理

Chemotherapy is one of the most important methods in the treatment of cancer. Cell cycle specific reagents are the main types of anti cancer drugs. Over expression of oncogenes, such as cyclin families, is one of the main molecular mechanisms of chemotherapy failure. According to our primary bioinformatic analysis, ehtyol may have the positive effects on G2/M-phase specific anti-cancer drugs activity. The possible underlying molecular mechanism may include: inhibiting the expression of cyclin D1 by epigenetic process and preventing cell from G1 cell cycle phase to S phase; accelerating cell into M phase from G2 phase. All these molecular events have been verified in our primary work. The present study want to observe the different effects of ethyol on different kinds of cell cycle specific anti cancer drugs in leukemia cell lines, such as acute monocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia and megakaryocytic leukemia. In order to exploring the underlying molecular mechanism of this synergism function, the effects of ethyol on DNA Methylation and histone acetylation level will be studied. Also, we will further put our efforts on apoptosis and key molecular in the cell cycle regulation process. The final purpose of this study is to give a rule in effective chemotherapy combination in the treatment of cancer.

化疗是肿瘤最主要治疗方法之一，细胞周期素为代表的癌基因过表达是化疗失败和肿瘤进展的重要分子病理学机制。本研究前期的生物信息学预测表明，依硫磷酸可增强G2/M期细胞周期特异性化疗药物的抗肿瘤作用。原因可能为，依硫磷酸可通过染色体表观基因修饰作用：①抑制周期素D1 表达，阻滞肿瘤细胞由G1 期进入S 期；②加速G2 期进入M 期，增强G2/M 期化疗药物杀瘤活性。此预测已初获验证。本研究拟以常见的急性髓系、单核、淋巴和巨核白血病细胞系为对象，观察依硫磷酸对常用非细胞周期和不同细胞周期类型化疗药物抗白血病作用的影响。从基因组甲基化和染色体组蛋白乙酰化修饰以及人类全基因组表达等，主要从DNA 甲基化和组蛋白乙酰化角度，探讨依硫磷酸增强细胞周期特异性化疗药物影响的分子机制，重点关注凋亡和细胞周期关卡基因的表达及调控。为提高化疗抗肿瘤作用的临床疗效提供指导。

中文摘要(500字以内)：.化疗是肿瘤最主要治疗方法之一，细胞周期素为代表的癌基因过表达是化疗失败和肿瘤进展的重要分子病理学机制。本研究前期的生物信息学预测表明，依硫磷酸可增强G2/M期细胞周期特异性化疗药物的抗肿瘤作用。原因可能为，依硫磷酸可通过染色体表观基因修饰作用：①抑制周期素D1 表达，阻滞肿瘤细胞由G1 期进入S 期；②加速G2 期进入M 期，增强G2/M 期化疗药物杀瘤活性。此预测已初获验证。本研究拟以常见的急性巨核白血病细胞系Dami和肝癌细胞系HepG2为对象，观察依硫磷酸对常用非细胞周期和不同细胞周期类型化疗药物抗白血病作用的影响。从基因组甲基化和染色体组蛋白乙酰化修饰以及人类全基因组表达等，主要从DNA 甲基化和组蛋白乙酰化角度，探讨依硫磷酸增强细胞周期特异性化疗药物影响的分子机制，重点关注凋亡和细胞周期关卡基因的表达及调控。为提高化疗抗肿瘤作用的临床疗效提供指导。结果发现，依硫磷酸可以诱导Dami细胞分化；促进转录因子GATA-1和NF-E2进入细胞核；增强TPO/MPL的信号通路传导；抑制细胞周期素CyclinD1基因和蛋白的表达。未来依硫磷酸有可能作为治疗CyclinD1高表达的恶性肿瘤的基础治疗药物，同时在促进血小板生产方面发挥重要作用。进一步的机制和疗效有待深入研究加以证实。