Aviram A, Rephaeli A, Shaklai M, Nudelman A, Ben-Dror I, Maron L, Rabizadeh E
Institute of Hematology, Rabin Medical Center, Tel Aviv University, Israel.
J Cancer Res Clin Oncol. 1997;123(5):267-71. doi: 10.1007/BF01208637.
Previously we have shown that pivaloyloxymethyl butyrate (AN-9), a pro-drug of butyric acid (BA), is a differentiation-inducing agent in a variety of cells. In this report, we demonstrate that AN-9 is a cytostatic but not cytotoxic agent in a myelomonocytic cell line (WEHI); thus, the cells were growth-arrested and differentiated. These late changes in the cells were preceded by changes in the expression of the early regulatory genes, c-myc and c-jun. Although initiation of all these events had already occurred after 1 h exposure to AN-9, the tumorigenicity of these cells tested in Balb/c mice was not affected. A marked reduction in the tumorigenicity of AN-9-treated cells was observed after 4 h of exposure. Exposure of the highly metastatic subclone of Lewis lung carcinoma (3LLD122) to AN-9 resulted in a very pronounced effect on the tumorigenicity of these cells tested in C57BL mice. Unlike WEHI cells, the tumorigenicity of 3LLD122 was almost completely diminished after 1 h of exposure. In both cell types a 10-fold higher concentration of BA did not affect the tumorigenicity of the cells as did AN-9.
先前我们已经表明，丁酸（BA）的前体药物新戊酰氧基甲基丁酸酯（AN-9）在多种细胞中是一种诱导分化剂。在本报告中，我们证明AN-9在髓单核细胞系（WEHI）中是一种细胞生长抑制剂而非细胞毒性剂；因此，细胞生长停滞并发生分化。这些细胞的晚期变化之前，早期调控基因c-myc和c-jun的表达发生了变化。尽管在暴露于AN-9 1小时后所有这些事件就已开始，但在Balb/c小鼠中测试这些细胞的致瘤性并未受到影响。在暴露4小时后，观察到经AN-9处理的细胞的致瘤性显著降低。将高转移性的Lewis肺癌亚克隆（3LLD122）暴露于AN-9，对在C57BL小鼠中测试的这些细胞的致瘤性产生了非常显著的影响。与WEHI细胞不同，暴露1小时后3LLD122的致瘤性几乎完全消失。在这两种细胞类型中，浓度比AN-9高10倍的BA对细胞的致瘤性没有影响。
