(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

Abstract

For decades, skin cancer incidence has increased, mainly due to oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of HOEC, [(+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate], isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 C14l cells without toxicity. PI3-K, ERK1/2 and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3-K, ERK1/2 and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP-1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is as a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure.

Protective Effects of Resveratrol against UVA-Induced Damage in ARPE19 Cells

“…UV irradiation has been reported to upregulate MAPK signaling pathways [ 28 ] and MAPK phosphorylation, including those of ERKs, JNKs and p38 kinase [ 7 , 28 , 29 ]. JNK and p38 activation are essential for UV-induced apoptosis, but activation of ERK, NF-κB, PI3K/Akt, and the mammalian target of rapamycin (mTOR) complex can be the surviving pathways against UV-induced death signaling [ 30 , 31 ]. However, ERK1/2 is also involved in oxidative-stress-induced VEGF upregulation [ 32 ], which may be related to choroidal neovascularization.…”

Inhibitory effects of tangeretin and trans-ethyl caffeate on the HMG-CoA reductase activity: Potential agents for reducing cholesterol levels

“…It is well known that tangeretin is a citrus flavonoid and have been reported to have anticancer and antitumor activities on Human mammary cells ( Depypere et al, 2000 ), human breast and colon cancer cells, leukaemia cancer cells HL60 ( Morley et al, 2007 ) and human gastric cancer AGS ( Dong et al, 2014 ). On the other hand, ethyl caffeate was reported to have anti-cancer activity against human ovarian cancer SKOV-3 cells ( Lee et al, 2014 ), human skin cancer ( Lim et al, 2014 ) and anti-inflammatory activity ( Chiang et al, 2005 ). Tangeretin has potency in anti-hypercholesterolemia activity ( Kuroskwa and Manthey, 2004 ).…”

In-vitro and in-vivo antimalarial activity of caffeic acid and some of its derivatives

“…This alarming situation highlights the urgent need to discover new antimalarial molecules. Natural phenolic compounds, commonly found in various plants, and some of their simple esters are known for several biological activities, such as anti‐inflammatory, antioxidant, anti‐diabetic, anti‐carcinoma, antibacterial and immunomodulatory . Among phenolic metabolites, caffeic acid and derivatives (such as chlorogenic) are the most frequently found and could be present in high quantities in some plants used as antimalarial traditional medicines, but also in foods (coffee beans, thyme, mint, wine, several fruits and vegetables…) …”