1,8-cineole prevents UVB-induced skin carcinogenesis by targeting the aryl hydrocarbon receptor

Abstract

1,8-cineole is a natural monoterpene cyclic ether present in Eucalyptus, and has been reported to exhibit anti-inflammatory and antioxidant effects. However, the preventive effect of 1,8-cineole on skin carcinogenesis and the molecular mechanism of action responsible remains unknown. In the present study, we investigated the effect of 1,8-cineole on UVB-induced skin carcinogenesis. 1,8-cineole inhibited UVB-induced cyclooxygenase-2 (COX-2) protein and mRNA expression and prostaglandin E2 (PGE2) generation in HaCaT cells. 1,8-cineole also inhibited phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and phosphorylation of its upstream kinases, c-Src and epidermal growth factor receptor (EGFR). Quantitative real-time RT-PCR (qRT-PCR) and drug affinity responsive target stability (DARTS) assay results showed that 1,8-cineole suppressed UVB-induced expression of a target gene of the aryl hydrocarbon receptor (AhR), cyp1a1, and directly binds to AhR. Knockdown of AhR suppressed COX-2 expression as well as phosphorylation of ERK1/2 in HaCaT cells. Furthermore, topical treatment of 1,8-cineole on mouse skin delayed tumor incidence and reduced tumor numbers, while inhibiting COX-2 expression in vivo. Taken together, these results suggest that 1,8-cineole is a potent chemopreventive agent that inhibits UVB-induced COX-2 expression by targeting AhR to suppress UVB-induced skin carcinogenesis.

NADPH Oxidase and Epidermal Growth Factor Receptor Are Promising Targets of Phytochemicals for Ultraviolet-Induced Skin Carcinogenesis

“…This step is essential for the activation of tyrosine kinase receptors, such as EGFR, via phosphorylation of the C-terminal tail. We have confirmed that UV irradiation upregulates EGFR phosphorylation at Tyr1068, Tyr1045, and Tyr845 in HaCaT cells [10,44].…”

“…Interestingly, UV irradiation brings about the dissociation of AhR and Src complexes, enabling Src to phosphorylate EGFR at Tyr845. Consequently, this phosphorylation increases cyp1a1 mRNA and COX-2 protein expression in HaCaT cells [ 44 ]. In short, UV-induced EGFR activation accelerates multiple signaling pathways involved in skin carcinogenesis.…”

“…The AhR signaling pathway is one of the major UVB-induced signaling pathways, and AhR mediates COX-2 overexpression. We demonstrated that 1,8-cineole, a monoterpene cyclic ether, inhibits c-Src-dependent EGFR activation induced by UVB, thereby suppressing the RAF-MEK1/2-ERK1/2 signaling pathway and cyp1a1 mRNA expression, a target gene of activated AhR [ 44 ]. This was demonstrated by the knockdown of AhR, which suppresses COX-2 expression in HaCaT cells.…”

Microencapsulation of eucalyptol in polyethylene glycol and polycaprolactone using particles from gas-saturated solutions

“…They further showed the modulatory effects of the monoterpenoid on inammatory mediators in cultured human lymphocytes 7 and the rationale for its use as a mucolytic agent in treatment of upper and lower airway diseases. 8 Other preclinical screening of eucalyptol against microbial and viral infections, 9,10 gastric ulcer and colitis, 11,12 hepatic injury and oxidative stress, 13,14 pain and pneumonia, 15,16 cancer and tumours, 17,18 cardiovascular and neurodegenerative diseases 19,20 have also been attributed to its inherent ability to modulate redox and inammation processes.…”

The Ginger Prophecy; A Review of the Underexplored Genus, Hedychium against Cancer

“…The main essential oils from H. ellipticum studied using GC-FID and GC-MS by [116] . Cineole or eucalyptol is found to supress expression of COX-2 through UVB-induced carcinogenesis in HaCaT cells and also inhibit generation of prostaglandin E2 in the cells [117] . Pinene also, is found to reduce the growth of tumour in mice [118] .…”