Maietta Immacolata, Martínez-Pérez Amparo, Álvarez Rosana, De Lera Ángel R, González-Fernández África, Simón-Vázquez Rosana
CINBIO, Immunology Group, Universidade de Vigo, 36310 Vigo, Spain.
Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain.
Pharmaceuticals (Basel). 2022 Jul 2;15(7):824. doi: 10.3390/ph15070824.
Epigenetic modifications could drive some of the molecular events implicated in proliferation, drug resistance and metastasis of pancreatic ductal adenocarcinoma (PDAC). Thus, epigenetic enzyme inhibitors could be the key to revert those events and transform PDAC into a drug-sensitive tumor. We performed a systematic study with five different epigenetic enzyme inhibitors (1, UVI5008, MS275, psammaplin A, and BIX01294) targeting either Histone Deacetylase (HDAC) 1 or 1/4, DNA methyltransferase 3a (DNMT3a), Euchromatic histone lysine methyltransferase 2 (EHMT2), or Sirtuin 1 (SIRT1), as well as one drug that restores the p53 function (P53R3), in three different human PDAC cell lines (SKPC-1, MIA PaCa-2, and BxPC-3) using 2D and 3D cell cultures. The synergistic effect of these antitumoral drugs with gemcitabine was tested and the most efficient combinations were characterized by RNA-seq. The inhibition of HDAC1/4 (MS275), HDAC1/4/SIRT1/DNMT3a (UVI5008) or EHMT2 (BIX01294) induced a significant reduction on the cell viability, even in gemcitabine-resistance cells. The combination of UVI5008 or MS275 with gemcitabine induced a synergistic effect at low concentration and the RNA-Seq analysis revealed some synergy candidate genes as potential biomarkers. Reverting aberrant epigenetic modifications in combination with gemcitabine offers an alternative treatment for PDAC patients, with an important reduction of the therapeutic dose.
表观遗传修饰可能驱动胰腺导管腺癌（PDAC）增殖、耐药和转移过程中涉及的一些分子事件。因此，表观遗传酶抑制剂可能是逆转这些事件并将PDAC转化为对药物敏感肿瘤的关键。我们使用二维和三维细胞培养，在三种不同的人PDAC细胞系（SKPC-1、MIA PaCa-2和BxPC-3）中，对五种不同的表观遗传酶抑制剂（1、UVI5008、MS275、沙马泊林A和BIX01294）进行了系统研究，这些抑制剂分别靶向组蛋白去乙酰化酶（HDAC）1或1/4、DNA甲基转移酶3a（DNMT3a）、常染色质组蛋白赖氨酸甲基转移酶2（EHMT2）或沉默调节蛋白1（SIRT1），以及一种恢复p53功能的药物（P53R3）。测试了这些抗肿瘤药物与吉西他滨的协同作用，并通过RNA测序对最有效的组合进行了表征。抑制HDAC1/4（MS275）、HDAC1/4/SIRT1/DNMT3a（UVI5008）或EHMT2（BIX01294）即使在吉西他滨耐药细胞中也能显著降低细胞活力。UVI5008或MS275与吉西他滨联合使用在低浓度下诱导了协同作用，RNA测序分析揭示了一些协同候选基因作为潜在生物标志物。与吉西他滨联合逆转异常表观遗传修饰为PDAC患者提供了一种替代治疗方法，可显著降低治疗剂量。
