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

Abstract

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.

Radix clematidis extract inhibits TPA-induced MMP-9 expression by suppressing NF-κB activation in MCF-7 human breast cancer cells

“…Previous studies have demonstrated that NF-κB is a molecular target in RCE treated cells (15,19). Our findings showed the molecular mechanism of RCE, and that RCE blocked the TPA-mediated activation of NF-κB pathway.…”

“…MMP-2, on the other hand, is usually expressed constitutively (13,14). Cytokine and 12-O-tetradecanoyl phorbol-13-acetate (TPA) treatments are capable of inducing MMP-9 expression via the activation of transcription factors such as NF-κB and activator protein-1 (AP-1) (15)(16)(17). Consequently, inhibiting MMP-9 expression and/or its upstream regulatory pathways is critical to the treatment of malignant tumors, including breast carcinoma.…”

HAb18G/CD147 Functions in Invasion and Metastasis of Hepatocellular Carcinoma

“…Downregulating or blocking tumor cell HAb18G/CD147 significantly decreased this invasive potential of HCC cells and also significantly attenuated the MMP production. MMP-2 and MMP-9 were previously reported to be involved in human hepatic tumorigenesis and metastasis (28). In this study, MMP (MMP-2 and MMP-9) gene silence in HCC cells also significantly inhibited the invasion in the coculture system, but its inhibitory effects were significantly weaker than not only HAb18G/CD147 silence in HCC cells but also MMP silence in fibroblasts.…”

Contribution of Major Hydrophilic and Lipophilic Antioxidants from Papaya Fruit to Total Antioxidant Capacity

“…Kang, et al [33] found that CA inhibited the activity of Fyn kinase, which belongs to the family of non-receptive proteins of tyrosine kinase, suppressing skin carcinogenesis, which suggests a chemo-preventive effect of this type of cancer. In a study performed by Chung et al [34], liver metastasis was reduced significantly, confirming the anti-tumoral and anti-metastatic effects of CA and caffeic acid phenethylester (CAPE). With respect to the antioxidant and anti-inflammatory capacity of ferulic acid, it has been observed that this acid has positive effects against Alzheimer when mice were treated with FA, reducing the activity of the coline acetyltransferase [35].…”