Differentiating effect of sodium butyrate on human hepatoma cell lines PLC/PRF/5, HCC‐M and HCC‐T

Saito, Hidetsugu; Morizane, Toshio; Watanabe, Tetsu; Kagawa, Tatehiro; Miyaguchi, Shingo; Kumagai, Naoya; Tsuchiya, Masaharu

doi:10.1002/ijc.2910480223

Cited by 52 publications

(37 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Butyric acid causes the upregulation of genes involved in cellular differentiation by inhibiting histone deacetylase activity 41 and has previously been reported to induce hepatocyte differentiation in human hepatoma cells. 42 Despite BA treatment having been considered for patients with leukemia and colon cancer, 6,7 its effective use as chemotherapeu- tic or chemopreventive agent is compromised 8 due to its short half-life. 6 To circumvent the problem of fast metabolism of butyrate monomers, analogues have been tested.…”

Section: Discussionmentioning

confidence: 99%

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

Kuroiwa-Trzmielina

Conti

Scolastici

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

Kuroiwa-Trzmielina

Conti

Scolastici

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Butyrate and its derivatives exert a number of antiproliferative effects on transformed cell lines in vitro, including decreased DNA replication leading to arrest of cell division in the G 1 phase, modification of cellular morphology, and alteration of gene expression consistent with differentiation. [78][79][80][81][82][83][84][85][86][87][88][89] The mechanism(s) of action proposed for these effects on differentiation are varied and are not fully understood, but are likely attributable in large part to its actions as a histone deacetylase (HDAC) inhibitor. Similarly, the G 1 -phase cell-cycle arrest induced by butyrate and related shortchain fatty acids is dependent on HDAC-inhibitory activity and the resulting inhibition of cyclin D1 expression 90 and induction of cyclin-dependent kinase p27.…”

Section: Org Frommentioning

confidence: 99%

A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus–associated lymphoid malignancies

Perrine

Hermine

Small

et al. 2006

Blood

268

179

View full text Add to dashboard Cite

“…Butyrate shows potent effects on growth arrest and differentiation in vitro in various malignant tumor cell lines, such as breast cancer cells, hepatoma cells, and others (2)(3)(4)(5). In colorectal cancer cells, butyrate inhibits cell growth and induces differentiation marker proteins such as alkaline phosphatase and carcinoembryonic antigen (6 -9).…”

mentioning

confidence: 99%

Butyrate Activates the WAF1/Cip1 Gene Promoter through Sp1 Sites in a p53-negative Human Colon Cancer Cell Line

Nakano

Mizuno²,

Sowa

et al. 1997

Journal of Biological Chemistry

377

295

View full text Add to dashboard Cite

Butyrate is a well known colonic luminal short chain fatty acid, which arrests cell growth and induces differentiation in various cell types. We examined the effect of butyrate on the expression of WAF1/Cip1, a potent inhibitor of cyclin-dependent kinases, and its relation to growth arrest in a p53-mutated human colon cancer cell line WiDr. Five millimolar butyrate completely inhibited the growth of WiDr and caused G 1 -phase arrest. WAF1/Cip1 mRNA was rapidly induced within 3 h by treatment with 5.0 mM butyrate, and drastic WAF1/Cip1 protein induction was detected. Using several mutant WAF1/Cip1 promoter fragments, we found that the butyrate-responsive elements are two Sp1 sites at ؊82 and ؊69 relative to the transcription start site. We also found that a TATA element at ؊46 and two overlapping consensus Sp1 sites at ؊60 and ؊55 are essential for the basal promoter activity of WAF1/Cip1. These findings suggest that butyrate arrests the growth of WiDr by activating the WAF1/Cip1 promoter through specific Sp1 sites in a p53-independent fashion.Butyrate is one of the most abundant short chain fatty acids in the large intestine, generated by bacterial fermentation of dietary fibers (1). Butyrate shows potent effects on growth arrest and differentiation in vitro in various malignant tumor cell lines, such as breast cancer cells, hepatoma cells, and others (2-5). In colorectal cancer cells, butyrate inhibits cell growth and induces differentiation marker proteins such as alkaline phosphatase and carcinoembryonic antigen (6 -9). Furthermore, butyrate arrests the cell cycle progression at the G 1 phase (9) and decreases c-myc oncogene expression in human colon cancer cell lines (9, 10). However, the precise mechanism of growth suppression by butyrate in colon cancer cells has not been clarified. WAF1/Cip1 protein potently inhibits the various G 1 cyclindependent kinases activities (11-13) by suppressing the phosphorylation of retinoblastoma (RB) protein, thereby supposedly inhibiting the G 1 -S phase transition (11,14). Besides its role as a kinase inhibitor, it has been reported recently that WAF1/ Cip1 at low doses assembles kinase complexes and promotes a kinase activity (15). Furthermore, the transcription of the WAF1/Cip1 gene is directly activated by wild-type p53 protein (16). Thus, WAF1/Cip1 could play a key role as a downstream mediator of the p53-induced cell growth arrest.Several studies have already shown the p53-independent induction of WAF1/Cip1 by serum, transforming growth factor ␤, and other differentiation-inducers (17)(18)(19)(20). In addition, butyrate has been reported to induce WAF1/Cip1 mRNA independently of p53 during differentiation of hematopoietic cells, hepatoma cells, and colon cancer cells in vitro (18,21). Butyrate can also dephosphorylate the retinoblastoma protein in mouse fibroblasts (22). To investigate the mechanism of butyrateinduced growth arrest, we used a human colon cancer cell line WiDr harboring a point mutation in p53 at codon 273 (23) and examined the effect of butyrate on t...

show abstract

Differentiating effect of sodium butyrate on human hepatoma cell lines PLC/PRF/5, HCC‐M and HCC‐T

Cited by 52 publications

References 20 publications

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus–associated lymphoid malignancies

Butyrate Activates the WAF1/Cip1 Gene Promoter through Sp1 Sites in a p53-negative Human Colon Cancer Cell Line

Contact Info

Product

Resources

About