Inhibition of Tumor Angiogenesis by Phloroglucinol Figure 1. Effect of phloroglucinol derivatives isolated from Ecklonia cava on cell toxicity of EPCs. (A) Chemical structure of phloroglucinol: a class of natural products containing 1,3,5-trihydroxybenzene as the basic moiety. (B) Immunophenotyping of cell monolayers derived from HUCB EPCs by fluorescence microscope. A representative image is shown for HUCB EPCs. Immunophenotyping revealed that EPCs expressed endothelial cells lineage antigens including CD31, VEGFR-2 (KDR), VWF, eNOS, p-eNOS and p-Akt. (C) After treatment of phloroglucinol in EPCs, cell viability was examined using an MTT assay. doi:10.1371/journal.pone.0033618.g001 progression [21]. Importantly, the mobilization of EPCs from the bone marrow microenvironment to the peripheral blood may be an attractive target for anti-cancer treatments [9,21,22,23]. This hypothesis explains why we were interested in understanding if the anti-tumor activities of phloroglucinol involve in inhibiting the bioactivities of EPCs and if these activities eventually suppress tumor growth and angiogenesis in the LLC-tumor-bearing mouse model. Phloroglucinol compounds, both synthetic as well as natural, have a wide range of industrial applications because of their various biological activities such as anti-inflammatory, anti- microbial, anticancer, enzyme inhibitory, anti-allergic, anti- oxidant, and neurodegenerative activities [1,2,3,24]. In general, hyperforin formulations, which are phloroglucinol derivatives, have been used to treat various types of cancer and precancerous tumors because they exert anti-proliferative bioactivities by activating the intrinsic apoptosis pathways of a panel of tumor cell lines, including carcinoma and leukemia cells as well as endothelial cells. Further, these formulations can be used to treat angioproliferative retinopathy and skin diseases, in which pathological angiogenesis occurs [25,26,27]. This study presents novel findings that oral administration of phloroglucinol signifi- cantly reduces de novo neovessel formation in LLC tumor tissue by affecting EPCs bioactivities including their migratory capability, PLoS ONE | www.plosone.org 3 April 2012 | Volume 7 | Issue 4 | e33618