Suppression of growth of hepatocellular carcinoma by sodium butyrate in vitro and in vivo

Abstract

Treatment of HuH-7 human hepatocellular carcinoma (HCC) cells with 1-10 mM sodium butyrate (SB) resulted in growth inhibition in a dose-dependent manner. At 3 mM and higher concentrations, SB caused nuclear fragmentation and DNA ladder formation characteristic of apoptosis. In the treated cells, the expression of p21 (WAF1/CIP1) increased and that of ␣-fetoprotein (AFP) decreased. These characteristic changes were also observed with 5 other human HCC cell lines with or without mutation of the p53 gene. The ability of these cells to form colonies in soft agar was suppressed by either pretreating the cells with SB prior to soft agar plating or incubating untreated cells in SB-containing soft agar. Direct injection of SB into tumors developed from HuH-7 cells in nude mice resulted in an increase in the p21 level, a decrease in the tumor size and an increase in the survival time of mice. When the inoculation of HuH-7 cells into nude mice was immediately followed by subcutaneous injection of SB, development of tumors was either significantly delayed or completely suppressed. These results suggest that SB induces cellular differentiation and suppresses growth and tumorigenicity of HCC cells in vitro and in vivo by a mechanism independent of p53 but possibly dependent on p21. Int.

Effects of sodium butyrate on expression of members of the IGF-binding protein superfamily in human mammary epithelial cells

“…Previous studies indicate that the effect of butyrate and other histone deacetylase inhibitors on cells closely corresponds to the effects of p21 Waf1/Cip1 expression in the regulation of G1 (Hunter & Pines 1994), S (Ogryzko et al 1997) and G2 (Coradini et al 1997, Lallemand et al 1999) phases of the cell cycle (Hassig et al 1997). The major mechanism for butyrate-induced cell cycle arrest is reported to be through upregulation of p21 Waf1/Cip1 in various cell systems, including hepatocellular carcinoma cells (Yamamoto et al 1998), colon cancer cells (Nakano et al 1997, Siavoshian et al 1997, Archer et al 1998, Litvak et al 1998, prostate cancer cells (Huang et al 1999) and breast cancer cells (Lallemand et al 1999). In contrast, Vaziri et al (1998) …”

“…It is a potent growth inhibitor and initiates cell differentiation in several cell types, including breast cancer cells in vitro (Coradini et al 1997, Velázquez et al 1997, Gleave et al 1998, Yamamoto et al 1998. Although the molecular mechanisms by which butyrate exerts its effects are still unclear, it is known to induce a number of alterations within the nucleus, including histone hyperacetylation (de Haan et al 1986, Archer & Hodin 1999.…”

Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But

“…Unfortunately, treatment failure is frequent and results in high recurrence rates with short survival times (5-7). Histone deacetylase inhibitors (HDACi), including sodium butyrate, are potent inducers of cell growth arrest, differentiation, or apoptosis in a variety of transformed cell lines, including hepatocellular carcinoma, and in intrahepatic metastasis-bearing animals (8,9). Their mechanism of action is based on their ability to inhibit the activity of histone deacetylase enzymes (HDACs); these enzymes, as opposed to histone acetyltransferases, are involved in the regulation of gene expression by determining the degree of acetylation of histones, the core proteins of the nucleosomal structure.…”

HDAC inhibitors effectively induce cell type-specific differentiation in human glioblastoma cell lines of different origin

“…It is well established that HDAC inhibitors exert differentiation effects on many types of cancer cells, including hepatocellular carcinoma (8,39,40), breast cancer (39) and human prostate cancer cells (41). Herein we demonstrated that the HDAC inhibitors 4-PB and TSA possess growth-inhibitory, unique differentiation and pro-apoptotic effects on human glioblastoma cell lines of different cellular origin.…”