Wang Chenyin, Hamacher Alexandra, Petzsch Patrick, Köhrer Karl, Niegisch Günter, Hoffmann Michèle J, Schulz Wolfgang A, Kassack Matthias U
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
Biological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany.
Cancers (Basel). 2020 Feb 3;12(2):337. doi: 10.3390/cancers12020337.
Occurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibitor decitabine (DAC) with the histone deacetylase inhibitor entinostat (ENT) in bladder cancer cells with different platinum sensitivities: J82, cisplatin-resistant J82CisR, and RT-112. Intermittent treatment of J82 cells with cisplatin resulted in the six-fold more cisplatin-resistant cell line J82CisR. Combinations of DAC and/or ENT plus cisplatin could not reverse chemoresistance. However, the combination of DAC and ENT acted cytotoxic in a highly synergistic manner as shown by Chou-Talalay analysis via induction of apoptosis and cell cycle arrest. Importantly, this effect was cancer cell-selective as no synergism was found for the combination in the non-cancerous urothelial cell line HBLAK. Expression analysis indicated that epigenetic treatment led to up-regulation of forkhead box class O1 (FoxO1) and further activated proapoptotic Bim and the cell cycle regulator p21 and reduced expression of survivin in J82CisR. In conclusion, the combination of DAC and ENT is highly synergistic and has a promising potential for therapy of bladder cancer, particularly in cases with platinum resistance.
膀胱癌中顺铂耐药现象频繁发生，会导致疾病进展。因此，对于化疗失败的患者而言，新型治疗方法具有迫切的医疗需求。本研究的目的是在具有不同铂敏感性的膀胱癌细胞系（J82、顺铂耐药的J82CisR和RT-112）中测试DNA甲基转移酶抑制剂地西他滨（DAC）与组蛋白去乙酰化酶抑制剂恩替诺特（ENT）的联合应用效果。用顺铂间歇性处理J82细胞，产生了对顺铂耐药性高6倍的细胞系J82CisR。DAC和/或ENT加顺铂的联合应用无法逆转化疗耐药性。然而，通过Chou-Talalay分析表明，DAC和ENT的联合应用具有高度协同的细胞毒性作用，可诱导细胞凋亡和细胞周期阻滞。重要的是，这种作用具有癌细胞选择性，因为在非癌性尿路上皮细胞系HBLAK中未发现该联合应用具有协同作用。表达分析表明，表观遗传治疗导致叉头框O1类（FoxO1）上调，并进一步激活促凋亡蛋白Bim和细胞周期调节因子p21，同时降低J82CisR中生存素的表达。总之，DAC和ENT的联合应用具有高度协同性，在膀胱癌治疗中具有广阔的应用前景，尤其是对于铂耐药的病例。
