Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.
Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.
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DOI：
10.1038/sj.bjc.6603511
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发表时间：
2007-01-15
影响因子：
8.8
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胰腺导管腺癌（PDAC）是一种致死性疾病，也是预期寿命最短的癌症之一。除手术治疗外，尚无有效的治疗方法。在这里，我们表明，4-苯基丁酸（4-PB），一种已知的和良好耐受的组蛋白脱乙酰酶（HDAC）的抑制剂，诱导高达70%的细胞凋亡在所有测试的细胞系（Panc 1，T4 M-4，科洛357，BxPc 3）。相比之下，它只在一半的测试细胞系中导致细胞周期停滞。该药物以浓度依赖性方式增加相邻T3 M-4细胞之间的间隙连接通讯，并有效抑制Panc 1、T4 M-4、科洛357和BxPc 3细胞中的细胞输出机制。因此，与吉西他滨联合使用时，4-PB显示出对BxPc 3和T3 M-4细胞凋亡诱导的过度累加效应（与单一药物治疗相比高达4.5倍），伴随着半胱天冬酶8、BH 3相互作用结构域死亡激动剂（Bid）和聚（ADP-核糖）聚合酶家族成员1（PARP）裂解的激活。虽然丝裂原活化蛋白激酶途径的抑制对细胞凋亡的暴发性诱导没有影响，但SP 600125对JNK途径的抑制完全消除了本研究首次报道的联合应用两种药物诱导的过度累加效应。
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.