Apoptosis and tumor remission in liver tumor xenografts by 4-phenylbutyrate.
4-phenylbutyrate (triButyrate trade mark, PB) a derivative of the short-chain fatty acid, butyrate, possesses anti-tumor activity in vitro in different tumor cell lines. Unlike most cytostatic compounds, PB possesses low toxicity. In order to evaluate possible clinical use of PB in cancer therapy, hepatocarcinoma (Hep3B) and hepatoblastoma (HepT1) cell lines, as well as xenografts derived from those in nude rats, were treated with PB in different dose (1-100 mM) and time regimens. Treatment with 10 mM of PB for 24 h (or 5 mM for 48 h) was shown to significantly inhibit Hep3B cell growth in vitro. The HepT1 cell line was more sensitive to PB treatment: already 1 mM of PB for 24 h significantly inhibited the growth of the cells. PB also resulted in regression of xenografts derived from these cell lines in vivo, when administrated by mini-pump with an intratumor catheter, yielding 20 micro mol of PB per cm3 of tumor volume per day. TUNEL assay and caspase-3 activity measurements suggested apoptosis to be the cell death mechanism in both cell lines and xenografts. Increased histones H3 and H4 acetylation was shown in both cells and xenografts, and the inhibition of histone deacetylase is proposed as the main trigger for the anti-tumor action of PB. Concomitant induction of p21Waf1/Cip1 expression was detected by RNase protection assay and Western blotting. Reduction in expression of alpha-fetoprotein was found both in Hep3B cells and xenografts, suggesting also a differentiation effect by PB.
Svechnikova
Irina
I
Department of Clinical Neuroscience, Experimental Alcohol and Drug Addiction Research Section, Karolinska Hospital, CMM, L8:01, S-171 76 Stockholm, Sweden.
Gray
Steven G
SG
Kundrotiene
Jurgita
J
Ponthan
Frida
F
Kogner
Per
P
Ekström
Tomas J
TJ
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor / Q000187:drug effects / Q000637:transplantation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007260:Infusion Pumps; D008113:Liver Neoplasms / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009363:Neoplasm Proteins; D010654:Phenylbutyrates; D000509:alpha-Fetoproteins; C075773:4-phenylbutyric acid; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases