Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autonóma de Mexico (UNAM), Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.
Oncol Rep. 2011 Feb;25(2):399-407. doi: 10.3892/or.2010.1086. Epub 2010 Dec 8.
Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases is a promising cancer therapy. Experimental data demonstrate that these inhibitors in combination do not only show synergy in antitumor effects but also in whole genome global expression. Ten pairs of pre- and post-treatment cervical tumor samples were analyzed by microarray analysis. Treatment for seven days with hydralazine and valproate (HV) in patients up-regulated 964 genes. The two pathways possessing the highest number of up-regulated genes comprised the ribosome protein and the oxidative phosphorylation pathways, followed by MAPK signaling, tight junction, adherens junction, actin cytoskeleton, cell cycle, focal adhesion, apoptosis, proteasome, Wnt signaling, and antigen processing and presentation pathways. Up-regulated genes by HV, clustered with down-regulated genes in untreated primary cervical carcinomas and were more alike as compared with up-regulated genes from untreated patients in terms of gene ontology. Increased acetylated p53 was also observed. Epigenetic therapy with HV leads to gene reactivation in primary tumors of cervical cancer patients as well as protein acetylation. A number of these reactivated genes have a definitive role as a tumor suppressors. The global expression pattern induced by HV suggests this therapy has an impact on pathways related to energy production which may promote apoptosis.
异常的 DNA 甲基化和组蛋白去乙酰化参与癌症的发生和发展；因此，通过 DNA 甲基化抑制剂和组蛋白去乙酰化酶抑制剂将其逆转是一种很有前途的癌症治疗方法。实验数据表明，这些抑制剂联合使用不仅在抗肿瘤作用方面具有协同作用，而且在全基因组的整体表达方面也具有协同作用。通过微阵列分析，对 10 对治疗前后的宫颈肿瘤样本进行了分析。用肼屈嗪和丙戊酸钠（HV）对患者进行为期 7 天的治疗，上调了 964 个基因。两条途径拥有最多上调的基因，包括核糖体蛋白和氧化磷酸化途径，其次是 MAPK 信号转导、紧密连接、黏着连接、肌动蛋白细胞骨架、细胞周期、焦点黏附、细胞凋亡、蛋白酶体、Wnt 信号转导和抗原处理和呈递途径。HV 上调的基因与未经处理的原发性宫颈癌中的下调基因聚类，与未经处理的患者相比，HV 上调的基因在基因本体论方面更相似。还观察到乙酰化 p53 的增加。用 HV 进行表观遗传治疗可导致宫颈癌患者的原发性肿瘤基因重新激活和蛋白质乙酰化。许多这些重新激活的基因具有作为肿瘤抑制因子的明确作用。HV 诱导的整体表达模式表明，这种治疗方法对与能量产生相关的途径有影响，可能促进细胞凋亡。
