hyperforin and Melanoma

Oxidative stress and the hypoxic microenvironment play a key role in the progression of human melanoma, one of the most aggressive skin cancers. The aim of our study was to evaluate the effect of

Topics: Antineoplastic Agents; Antioxidants; Bridged Bicyclo Compounds; Humans; Hypericum; Hypoxia; Melanoma; Neoplastic Processes; Phloroglucinol; Plant Extracts; Terpenes; Tumor Microenvironment

We analyzed the relationship among microvessel density (MVD) and tumor infiltrating cells in cutaneous malignant melanoma. We also studied the effect of hyperforin on tumor- and endothelial cell growth in vitro and in vivo. The density of lymphocyte subpopulations, macrophages, dendritic cells and CD34 + microvessels was determined by immunohistochemistry in primary tumor samples from 52 patients with melanoma thicker than 1 mm. The antiproliferative effect of hyperforin was studied on 16 human- and 7 rat cell lines and on human dermal microvascular endothelial cells (HDMEC). Intratumoral MVD did not show significant association with infiltration for any of these cell types. In the case of peritumoral reactive cell densities analyzed in the whole patient population, significant correlation was found with CD3 + T-cell density. This association was stronger in melanomas >4.0 mm and in visceral metastatic tumors. In these subgroups similar phenomenon was observed for CD8 + cells. We found significant correlation of MVD with CD68 + macrophage density only in the highest thickness category, and weak associations with B-cell and dendritic cell infiltration in visceral metastatic cases. MVD did not vary significantly in tumors categorized according to thickness, location, ulceration or histological type. However, both intratumoral MVD and macrophage infiltration were significantly higher in male patients compared to females. Hyperforin inhibited tumor cell proliferation and induced apoptosis. In vitro, it blocked capillary formation of HDMEC on a complex extracellular matrix. Furthermore, hyperforin reduced proliferation of HDMEC, without displaying toxic effects or inducing apoptosis. In Wistar rats hyperforin inhibited tumor growth and reduced tumor vascularization. Since the net outcome of the enrichment in tumor-infiltrating host cells and in tumor vascularization cannot be easily predicted, further clinicopathological studies are needed on human skin melanoma patients. Hyperforin holds the promise of being an interesting antineoplastic and antiangiogenic agent with low toxicity.

Topics: Angiogenesis Inhibitors; Animals; Antigens, CD34; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds; Cell Line, Tumor; Cell Proliferation; Dendritic Cells; Female; Humans; Lymphocyte Subsets; Macrophages; Male; Melanoma; Microcirculation; Neovascularization, Pathologic; Phloroglucinol; Rats; Rats, Wistar; Sex Factors; Skin Neoplasms; Terpenes