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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 activi¬ties 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 μg/mL) and CAPE (5 μg/mL) suppressed phorbol 12‐myristate 13‐acetate (PMA) ‐in¬duced MMP‐9 expression by inhibiting the function of NF‐κB, 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 antimetastatic 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‐κB as well as MMP‐9 catalytic activity.—Chung, T.‐W., Moon, S.‐K., Chang, Y.‐C., Ko, J.‐H., Lee, Y.‐C., Cho, G., Kim, S.‐H., Kim, J.‐G., Kim, C.‐H. 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. FASEBJ . 18, 1670–1681 (2004)
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Cites
Activators and target genes of Rel/NF-κB transcription factors
Pahl, H. L. (1999) · Oncogene · doi:10.1038/sj.onc.1203239 · Cited by 3,727
Cited by
Liu, G.-H., Qu, J., & Shen, X. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.01.002 · Cited by 697
Minor components of pulses and their potential impact on human health
Campos-Vega, R., Loarca-Piña, G., & Oomah, B. D. (2010) · Food Research International · doi:10.1016/j.foodres.2009.09.004 · Cited by 530
Weng, C.-J., & Yen, G.-C. (2012) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2011.03.001 · Cited by 485
Surh, Y.-J., Kundu, J. K., Na, H.-K., & Lee, J.-S. (2005) · The Journal of Nutrition · doi:10.1093/jn/135.12.2993s · Cited by 363
Chen, J., Wang, Q., Fu, X., Huang, X., Chen, X., Cao, L., Chen, L., Tan, H., Li, W., Bi, J., et al. (2009) · Hepatology Research · doi:10.1111/j.1872-034x.2008.00449.x · Cited by 342
Metadata
- Authors
- Chung, T., Moon, S., Chang, Y., Ko, J., Lee, Y., Cho, G., Kim, S., Kim, J., & Kim, C.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2004-11
- Volume
- 18
- Issue
- 14
- Pages
- 1670-1681
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1978272694
- Cited by
- 456
- References
- 1
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- closed
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- Chung, T., Moon, S., Chang, Y., Ko, J., Lee, Y., Cho, G., Kim, S., Kim, J., & Kim, C. (2004). 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. The FASEB Journal. https://doi.org/10.1096/fj.04-2126com
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