Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism.
Our previous studies have clearly shown that the angiogenic enzymes, matrix metalloproteinase (MMP) -2/9, are directly involved in human hepatic tumorigenesis and metastasis and suggest that the MMP-2/9 inhibitors, which have dual inhibitory activities on enzyme activity and transcription, represent the best candidates for achieving tumor regression. Many anti-cancer drugs have strong cellular cytotoxicity and side effects, indicating that strong anti-cancer drugs that have no or minimal cytotoxicity and side effects need to be developed. The specific aim of the present study was to develop powerful anti-cancer drugs with specific tumor regression and anti-metastatic potential having the dual inhibitory activities of specific MMP-2 and -9 enzyme activities and gene transcription at the molecular level. Caffeic acid (CA), a strong and selective MMP-9 activity and transcription inhibitor, was isolated from the plant Euonymus alatus and its derivative, caffeic acid phenethyl ester (CAPE), was synthesized. CA and CAPE selectively inhibited MMP-2 and -9 but not -1, -3, -7, or cathepsin K. Treatment of HepG2 cells with CA (100 microg/mL) and CAPE (5 microg/mL) suppressed phorbol 12-myristate 13-acetate (PMA) -induced MMP-9 expression by inhibiting the function of NF-kappaB, but not AP-1. We confirmed that CA and CAPE suppressed the growth of HepG2 tumor xenografts in nude mice in vivo. The subcutaneous and oral administrations of CA and CAPE significantly reduced the liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the anti-metastatic and anti-tumor effects of CA and CAPE are mediated through the selective suppression of MMP-9 enzyme activity and transcriptional down-regulation by the dual inhibition of NF-kappaB as well as MMP-9 catalytic activity.
Chung
Tae-Wook
TW
National Research Laboratory for Glycobiology and Department of Biochemistry and Molecular Biology, Dongguk University College of Oriental Medicine, Kyungju, Kyungbuk, Korea.
Moon
Sung-Kwon
SK
Chang
Young-Chae
YC
Ko
Jeong-Heon
JH
Lee
Young-Choon
YC
Cho
Gun
G
Kim
Soo-Hyun
SH
Kim
Jong-Guk
JG
Kim
Cheorl-Ho
CH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009362:Neoplasm Metastasis; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D002109:Caffeic Acids; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D020780:Matrix Metalloproteinase 9; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; C040048:caffeic acid