Kuroiwa-Trzmielina Joice, de Conti Aline, Scolastici Clarissa, Pereira Douglas, Horst Maria Aderuza, Purgatto Eduardo, Ong Thomas Prates, Moreno Fernando Salvador
Laboratory of Diet, Nutrition and Cancer, University of São Paulo, São Paulo, Brazil.
Int J Cancer. 2009 Jun 1;124(11):2520-7. doi: 10.1002/ijc.24212.
Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticarcinogenic agent. However, its short half-life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of "resistant hepatocyte" model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (p < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB-induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways.
肝细胞癌（HCC）的发病率和死亡率在全球十大癌症中名列前茅。丁酸（BA）是组蛋白去乙酰化酶抑制剂（HDACi）的一种，已被提议作为一种抗癌剂。然而，其半衰期短是一个治疗限制。三丁酸甘油酯（TB）作为一种提议的BA前药，可以规避这个问题。为了研究TB在化学预防方面的有效性，在肝癌发生的“抗性肝细胞”模型的初始阶段用该化合物处理大鼠，并评估细胞和分子参数。TB抑制（p<0.05）肝前体病变（PNL）的发展，包括那些被认为是HCC进展部位的持续性病变。TB增加（p<0.05）PNL重塑，即它们倾向于消失的过程。TB没有抑制PNL中的细胞增殖，但诱导（p<0.05）重塑细胞中的细胞凋亡。与对照组相比，用TB处理的大鼠肝脏中BA水平升高（p<0.05），表明其作为前药的有效性。研究了TB诱导肝癌化学预防的分子机制。TB特异性地增加（p<0.05）PNL中肝细胞核组蛋白H3K9的高乙酰化和p21蛋白表达，这可能与HDAC的抑制作用有关。此外，它降低（p<0.05）了具有异常细胞质p53积累的持续性PNL的频率，这种改变与恶性程度增加有关。我们研究中观察到的原始数据支持TB作为BA前药和HDACi在肝癌化学预防中的有效性。除了组蛋白乙酰化和p21表达恢复外，与TB抗癌作用相关的分子机制也可能与p53途径的调节有关。
