Eugenol Causes Melanoma Growth Suppression through Inhibition of E2F1 Transcriptional Activity

Abstract

Metastatic malignant melanoma is an extremely aggressive cancer, with no currently viable therapy. 4-Allyl-2-methoxyphenol (eugenol) was tested for its ability to inhibit proliferation of melanoma cells. Eugenol but not its isomer, isoeugenol (2-methoxy-4-propenylphenol), was found to be a potent inhibitor of melanoma cell proliferation. In a B16 xenograft study, eugenol treatment produced a significant tumor growth delay (p = 0.0057), an almost 40% decrease in tumor size, and a 19% increase in the median time to end point. More significantly, 50% of the animals in the control group died from metastatic growth, whereas none in the treatment group showed any signs of invasion or metastasis. Eugenol was well tolerated as determined by measurement of bodyweights. Examination of the mechanism of the antiproliferative action of eugenol in the human malignant melanoma cell line, WM1205Lu, showed that it arrests cells in the S phase of the cell cycle. Flow cytometry coupled with biochemical analyses demonstrated that eugenol induced apoptosis. cDNA array analysis showed that eugenol caused deregulation of the E2F family of transcription factors. Transient transfection assays and electrophoretic mobility shift assays showed that eugenol inhibits the transcriptional activity of E2F1. Overexpression of E2F1 restored about 75% of proliferation ability in cultures. These results indicate that deregulation of E2F1 may be a key factor in eugenol-mediated melanoma growth inhibition both in vitro and in vivo. Since the E2F transcription factors provide growth impetus for the continuous proliferation of melanoma cells, these results suggest that eugenol could be developed as an E2F-targeted agent for melanoma treatment.

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

“…Noteworthy, the inhibition of either E2F1 expression or E2F1 transcriptional activity was also reported to enhance the sensitivity of several cell types to apoptotic stimuli, 36,37 and blocking of E2F1 expression in vivo led to an increase of p53-independent apoptosis in UVB-irradiated mouse epidermis. 38 Puga and colleagues observed a reduced E2F1 expression in livers of AHR-deficient mice, indicating that the AHR is required for basal E2F1 expression.…”

Antifungal activity of eugenol against Botrytis cinerea

“…Eugenol (4-allyl-2-methoxyphenol) is a naturally occurring phenolic compound which is used as a food flavor and fragrance agent. It is a major component of clove oil and is also present in the essential oils or extracts of many other plants, including cinnamon, basil, and nutmeg (Ghosh et al, 2005). Eugenol has been reported to inhibit the growth of Escherichia coli, Listeria monocytogenes and Lactobacillus sakei (Blaszyk & Holley, 1998;Gill & Holley, 2004) and also exhibits antifungal activity against wood decay fungi ( Tsair-Bor & Shang-Tzen, 2008).…”

Phenylpropanoids, Eugenol Scaffold, and Its Derivatives as Anticancer

“…It has been reported that EU is a phenolic compound that induces apoptosis in human colon cancer cells [16]. The antiproliferative activity of EU against melanoma [17], leukemia [18], gastric [19], skin tumor [20], and prostate cancer [21] cells has been confirmed by many researchers. Structure of phenylprepanoids, eugenol scaffold and its derivatives as anticancer as Fig.…”

“…Since the E2F transcription factors provide growth for the continuous proliferation of melanoma cells, these results suggest that EU could be developed as an E2F-targeted agent for melanoma treatment [17]. Examination of the mechanism of the anti-proliferative action of EU in the human malignant melanoma cell line, WM1205Lu, showed that it arrests cells in the S phase of the cell cycle.…”