Suppression of growth of hepatocellular carcinoma by sodium butyrate in vitro and in vivo.
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 (WAFI/CIPI) increased and that of alpha-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 viva by a mechanism independent of p53 but possibly dependent on p21.
Yamamoto
H
H
First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Fujimoto
J
J
Okamoto
E
E
Furuyama
J
J
Tamaoki
T
T
Hashimoto-Tamaoki
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D014407:Tumor Cells, Cultured
D002087:Butyrates; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020148:Butyric Acid