Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in coffee and reportedly has anticancer activities. However, the underlying molecular mechanisms and targeted p ...

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Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in coffee and reportedly has anticancer activities. However, the underlying molecular mechanisms and targeted proteins involved in the suppression of carcinogenesis by caffeic acid are not fully understood. In this study, we report that caffeic acid significantly inhibits colony formation of human skin cancer cells and EGF-induced neoplastic transformation of HaCaT cells dose-dependently. Caffeic acid topically applied to dorsal mouse skin significantly suppressed tumor incidence and volume in a solar UV (SUV)-induced skin carcinogenesis mouse model. A substantial reduction of phosphorylation in mitogen-activated protein kinase signaling was observed in mice treated with caffeic acid either before or after SUV exposure. Caffeic acid directly interacted with ERK1/2 and inhibited ERK1/2 activities in vitro. Importantly, we resolved the cocrystal structure of ERK2 complexed with caffeic acid. Caffeic acid interacted directly with ERK2 at amino acid residues Q105, D106, and M108. Moreover, A431 cells expressing knockdown of ERK2 lost sensitivity to caffeic acid in a skin cancer xenograft mouse model. Taken together, our results suggest that caffeic acid exerts chemopreventive activity against SUV-induced skin carcinogenesis by targeting ERK1 and 2 (1).

Previous work from our laboratory showed that the mechanism of crude-honey induced apoptosis in colon cancer cells. Since phenolic constituents of honey were attributed to its apoptosis-inducing ability, we studied caffeic acid, one of the phenolic constituents of honey, induced effect on colon cancer cells. Antiproliferative effect of caffeic acid was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. MTT assay signified the antiproliferative nature of caffeic acid against the HCT 15 colon cancer cells. A time-dependent inhibition of colony formation was evident with caffeic acid treatment. Cell-cycle analysis of caffeic acid- (CA-) treated cells indicated increasing accumulation of cells at sub-G(1) phase. Photomicrograph images of treated cells showed membrane blebbing and cell shrinkage. Yo-pro-1 staining of caffeic-acid-treated cells confirmed apoptosis in dose- and time-dependent manner. Increasing ROS generation and reduction in the mitochondrial membrane potential were also accompanied in the caffeic acid-induced apoptosis. This work will promote caffeic acid as a likely candidate in the chemoprevention of colon cancer (2).

Hormesis is an adaptive response to a variety of oxidative stresses that renders cells resistant to harmful doses of stressing agents. Caffeic acid (CaA) is an important antioxidant that has protective effects against DNA damage caused by reactive oxygen species (ROS). However, whether CaA-induced protection is a hormetic effect remains unknown, as is the molecular mechanism that is involved. We found that a low concentration (10 μM) of CaA increased human liver L-02 cell viability, attenuated hydrogen peroxide (H2O2)-mediated decreases in cell viability, and decreased the extent of H2O2-induced DNA double-strand breaks (DSBs). In L-02 cells exposed to H2O2, CaA treatment reduced ROS levels, which might have played a protective role. CaA also activated the extracellular signal-regulated kinase (ERK) signal pathway in a time-dependent manner. Inhibition of ERK by its inhibitor U0126 or by its specific small interfering RNA (siRNA) blocked the CaA-induced improvement in cell viability and the protective effects against H2O2-mediated DNA damage. This study adds to the understanding of the antioxidant effects of CaA by identifying a novel molecular mechanism of enhanced cell viability and protection against DNA damage (3).

Caffeic acid has an antibacterial enhancing effect in 3 groups of bacteria (4).

References________________________________

(1) Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis
Ge Yang, Yang Fu, Margarita Malakhova, Igor Kurinov, Feng Zhu, Ke Yao, Haitao Li, Hanyong Chen, Wei Li, Do Young Lim, Yuqiao Sheng, Ann M. Bode, Ziming Dong, Zigang Dong
Cancer Prev Res (Phila) Author manuscript; available in PMC 2015 Oct 1.
Published in final edited form as: Cancer Prev Res (Phila). 2014 Oct; 7(10): 1056–1066. Published online 2014 Aug 7. doi: 10.1158/1940-6207.CAPR-14-0141

(2) Growth Inhibition by Caffeic Acid, One of the Phenolic Constituents of Honey, in HCT 15 Colon Cancer Cells - Saravana Kumar Jaganathan
ScientificWorldJournal. 2012

(3) Caffeic acid improves cell viability and protects against DNA damage: involvement of reactive oxygen species and extracellular signal-regulated kinase
Y. Li, L.J. Chen, F. Jiang, Y. Yang, X.X. Wang, Z. Zhang, Z. Li, L. Li
Braz J Med Biol Res. 2015 Jun; 48(6): 502–508. Published online 2015 Mar 27. doi: 10.1590/1414-431X20143729  

(4) Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol.
Lima VN, Oliveira-Tintino CD, Santos ES, Morais LP, Tintino SR, Freitas TS, Geraldo YS, Pereira RL, Cruz RP, Menezes IR, Coutinho HD.

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