Lea Michael A, Ibeh Chinwe, Shah Neel, Moyer Mary P
Department of Biochemistry and Molecular Biology, UMDNJ - New Jersey Medical School, Newark, New Jersey 07103, USA.
Anticancer Res. 2007 Mar-Apr;27(2):741-8.
The MAP kinase pathway inhibitor U0126 in combination with butyrate promotes differentiation in some colon cancer cell lines. We examined several inhibitors of histone deacetylase (HDAC) in combination with U0126 and other protein kinase inhibitors to see if these effects are general properties of HDAC inhibitors or butyrate alone. Alkaline phosphatase and peptidase activities were examined as markers for cellular differentiation in the human colon cancer cell lines Caco-2 and HT29 and the minimally transformed NCM460. Several HDAC inhibitors caused greater increases of alkaline phosphatase in the cancer cells than in NCM460, in which butyrate was the only HDAC inhibitor that caused a consistent increase. Unlike the JNK and PKC inhibitors examined, the MEK 1/2 inhibitor U0126 induced alkaline phosphatase activity in Caco-2 as a single agent and caused additive effects with HDAC inhibitors. The PI-3 kinase inhibitor LY294002 had little effect alone but enhanced the response of most HDAC inhibitors as did the raf inhibitor GW5074. In addition to butyrate, several HDAC inhibitors can induce differentiation in colon cancer cells and the responses may be enhanced by U0126, GW5074 and LY294002.
丝裂原活化蛋白激酶（MAP）激酶途径抑制剂U0126与丁酸盐联合使用可促进某些结肠癌细胞系的分化。我们研究了几种组蛋白脱乙酰酶（HDAC）抑制剂与U0126及其他蛋白激酶抑制剂联合使用的情况，以确定这些作用是HDAC抑制剂的普遍特性还是仅为丁酸盐的特性。在人结肠癌细胞系Caco-2、HT29和低转化的NCM460中，检测了碱性磷酸酶和肽酶活性作为细胞分化的标志物。几种HDAC抑制剂在癌细胞中引起的碱性磷酸酶增加幅度大于在NCM460中，在NCM460中丁酸盐是唯一能持续引起增加的HDAC抑制剂。与所检测的JNK和PKC抑制剂不同，MEK 1/2抑制剂U0126单独作用时可诱导Caco-2中的碱性磷酸酶活性，并与HDAC抑制剂产生相加效应。PI-3激酶抑制剂LY294002单独作用时几乎没有效果，但与raf抑制剂GW5074一样，可增强大多数HDAC抑制剂的反应。除丁酸盐外，几种HDAC抑制剂可诱导结肠癌细胞分化，且U0126、GW5074和LY294002可能会增强这种反应。
