Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis.
Caffeic acid phenethyl ester (CAPE) inhibits the growth of tumor cells and is a known inhibitor of nuclear factor kappa beta (NF-kappaB), which is constitutively active in cholangiocarcinoma (CCH) cells. We evaluated the effects of CAPE on CCH growth both in vitro and in vivo. Inhibition of NF-kappaB DNA-binding activity was confirmed in nuclear extracts treated with CAPE at 50, 40 and 20 microM. CAPE decreases the expression of NF-kappaB1 (p50) and RelA (p65). CAPE decreased the growth of a number of CCH cells but not normal cholangiocytes. Cell cycle decrease was seen by a decrease in PCNA protein expression and the number of BrdU-positive cells treated with CAPE at 20 microM compared to vehicle. Inhibition of growth and increased cell cycle arrest of Mz-ChA-1 cells by CAPE were coupled with increased apoptosis. Bax expression was increased, whereas Bcl-2 was decreased in cells treated with CAPE compared to vehicle. In vivo studies were performed in BALB/c nude (nu/nu) mice implanted subcutaneously with Mz-ChA-1 cells and treated with daily IP injections of DMSO or CAPE (10 mg/kg body weight in DMSO) for 77 days. Tumor growth was decreased and tumor latency was increased 2-fold in CAPE compared to vehicle-treated nude mice. In tumor samples, decreased CCH growth by CAPE was coupled with increased apoptosis. CAPE both in vivo and in vitro decreases the growth of CCH cells by increasing apoptosis. These results demonstrate that CAPE might be an important therapeutic tool in the treatment of CCH.
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Paolo
P
Onori
Sharon
S
DeMorrow
Eugenio
E
Gaudio
Antonio
A
Franchitto
Romina
R
Mancinelli
Julie
J
Venter
Shelley
S
Kopriva
Yoshiyuki
Y
Ueno
Domenico
D
Alvaro
Jennifer
J
Savage
Gianfranco
G
Alpini
Heather
H
Francis
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000032:analysis; D002109:Caffeic Acids / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003603:Cytotoxins / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D009929:Organ Size; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000187:drug effects; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D014408:Biomarkers, Tumor; D002109:Caffeic Acids; D003603:Cytotoxins; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D004247:DNA; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D004121:Dimethyl Sulfoxide