2-4-3--5--tetrahydroxystilbene and Melanoma

Tumor angiogenesis, growth and metastasis are three closely related processes. We therefore explored the effects of (-)-oleocanthal (OC) on the three processes in melanoma and investigated underlying mechanisms. In vitro, OC suppressed proliferation, migration, invasion and induced apoptosis in melanoma cells. In addition, OC inhibited proliferation, migration, invasion and tube formation in human umbilical vascular endothelial cells. In vivo, it exhibited potent activity in suppressing tumor growth in a subcutaneous xenograft model. Furthermore, OC suppressed proliferation and angiogenesis as measured by immunohistochemical staining of Ki-67 and CD31. In addition, OC was found to inhibit metastasis of melanoma in a lung metastasis model. Mechanistically, OC significantly suppressed signal transducer and activator of transcription 3 (STAT3) phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity. OC also downregulated STAT3 target genes, including Mcl-1, Bcl-xL, MMP-2, MMP-9, VEGF, which are involved in apoptosis, invasion and angiogenesis of melanoma. These results support further investigation of OC as a potential anti-melanoma drug.

Topics: Aldehydes; Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cells, Cultured; Cyclopentane Monoterpenes; Human Umbilical Vein Endothelial Cells; Humans; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Phenols; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Oleocanthal is one of the phenolic compounds of extra virgin olive oil with important anti-inflammatory properties. Although its potential anticancer activity has been reported, only limited evidence has been provided in cutaneous malignant melanoma. The present study is aimed at investigating the selective in vitro antiproliferative activity of oleocanthal against human malignant melanoma cells. Since oleocanthal is not commercially available, it was obtained as a pure standard by direct extraction and purification from extra virgin olive oil. Cell viability experiments carried out by WST-1 assay demonstrated that oleocanthal had a remarkable and selective activity for human melanoma cells versus normal dermal fibroblasts with IC50s in the low micromolar range of concentrations. Such an effect was paralleled by a significant inhibition of ERK1/2 and AKT phosphorylation and downregulation of Bcl-2 expression. These findings may suggest that extra virgin olive oil phenolic extract enriched in oleocanthal deserves further investigation in skin cancer.

Topics: Aldehydes; Cell Line, Tumor; Cell Survival; Cyclopentane Monoterpenes; Down-Regulation; Humans; Inhibitory Concentration 50; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Olive Oil; Oncogene Protein v-akt; Phenols; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms