Anti-proliferative activity of fenretinide in human hepatoma cells in vitro and in vivo.
N-(4-hydroxyphenyl)-retinamide (fenretinide) is a synthetic derivative of all-trans-retinoic acid and induces apoptosis in several cancer cell lines. We determined the anti-cancer activity of fenretinide using human hepatoma cell lines, Bel-7402, HepG2 and Smmc-7721. An in-vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that fenretinide exhibited growth inhibition in these cell lines, with IC50 values ranging from 13.1 to 15.5 micromol/l. In Bel-7402 cells, apoptosis with 15 micromol/l fenretinide for 0 and 48 h was 3 and 48%, respectively. In-vivo studies using the Bel-7402 xenografted athymic mouse model showed tumor inhibition rates ranging from 37.2 to 57.2%, with fenretinide administration once per 3 days at the rate of 25-100 mg/kg. Western blot analysis further showed down-regulation of procaspase-3, X-linked inhibitor of apoptosis protein and poly(ADP-ribose) polymerase cleavage in Bel-7402 cells treated with 15 mumol/l fenretinide for 48 h. Overexpression of p53 was observed in a time-dependent manner, along with a decrease in the Bcl-2/Bax ratio. Depolarized mitochondrial membranes were found in fenretinide-induced apoptotic cells, in a time-dependent manner. We conclude that fenretinide effectively inhibits the proliferation of Bel-7402, both in vitro and in vivo. Both procaspase-3 and p53-mediated apoptotic pathways are involved in its potent anti-cancer activity.
Shentu
Jianzhong
J
First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PRC.
Zhang
Bo
B
Fan
Lingling
L
He
Qioajun
Q
Yang
Bo
B
Chen
Zhi
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology* / Q000627:therapeutic use; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017313:Fenretinide