Phloroglucinol Inhibits the Bioactivities of Endothelial Progenitor Cells and Suppresses Tumor Angiogenesis in LLC-Tumor-Bearing Mice Yi-Hong Kwon2, Seok-Yun Jung1, Jae-Won Kim2, Sang-Hun Lee1, Jun-Hee Lee1, Boo-Yong Lee2*, Sang- 1 Mo Kwon * 1 Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, School of Medicine, Medical Research Institute, Pusan National University, Gyeongsangnam-do, Republic of Korea, 2 Department of Biomedical Science, Laboratory for Functional Foods and Nutrigenomics, Department of Food Science and Biotechnology, CHA University, Kyunggi, Republic of Korea Abstract Background: There is increasing evidence that phloroglucinol, a compound from Ecklonia cava, induces the apoptosis of cancer cells, eventually suppressing tumor angiogenesis. Methodology/Principal Findings: This is the first report on phloroglucinol’s ability to potentially inhibit the functional bioactivities of endothelial progenitor cells (EPCs) and thereby attenuate tumor growth and angiogenesis in the Lewis lung carcinoma (LLC)-tumor-bearing mouse model. Although Phloroglucinol did not affect their cell toxicity, it specifically inhibited vascular endothelial growth factor (VEGF) dependent migration and capillary-like tube formation of EPCs. Our matrigel plug assay clearly indicated that orally injected phloroglucinol effectively disrupts VEGF-induced neovessel formation. Moreover, we demonstrated that when phloroglucinol is orally administered, it significantly inhibits tumor growth and angiogenesis as well as CD452/CD34+ progenitor mobilization into peripheral blood in vivo in the LLC-tumor- bearing mouse model. Conclusions/Significance: These results suggest a novel role for phloroglucinol: Phloroglucinol might be a modulator of circulating EPC bioactivities, eventually suppressing tumorigenesis. Therefore, phloroglucinol might be a candidate compound for biosafe drugs that target tumor angiogenesis. Citation: Kwon Y-H, Jung S-Y, Kim J-W, Lee S-H, Lee J-H, et al. (2012) Phloroglucinol Inhibits the Bioactivities of Endothelial Progenitor Cells and Suppresses Tumor Angiogenesis in LLC-Tumor-Bearing Mice. PLoS ONE 7(4): e33618. doi:10.1371/journal.pone.0033618 Editor: Rana Pratap Singh, Jawaharlal Nehru University, India Received September 30, 2011; Accepted February 14, 2012; Published April 9, 2012 Copyright: 2012 Kwon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a National Research Foundation grant funded by the Korea government (2010-0020260) and a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A100322). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: smkwon323@pusan.ac.kr (S-MK); bylee@cha.ac.kr (B-YL) Introduction Phloroglucinol is a compound from Ecklonia cava, a species of brown alga. Recently, this biomolecule has attracted attention for drug synthesis because of its anti-inflammatory [1], anti-microbial, anti-allergic, and antioxidant activities [2,3] and human immu- nodeficiency virus (HIV)-1 reverse transcriptase and protease inhibitor activities [4]. However, little is known about its effect on progenitor cell-mediated tumor angiogenesis. Tumor angiogenesis is a pivotal step in tumor growth because blood vessels generated by this pathophysiological process supply cancer cells with nutrients and oxygen, which are indispensable for the proliferation and survival of these cells. Emerging data shows that adequate inhibition of tumor angiogenesis can attenuate tumor growth [5]. Recently, the screening of natural products for anti-cancer properties has come into focus because these biomolecules cause few side-effects and have strong specific tumor cell targeting effects [6,7,8]. During tumor angiogenesis as well as vascular injury, circulating progenitor cells are dynamically mobilized from the bone marrow into the circulating blood, leading to vasculature remodeling [9,10,11,12,13]. Neovessel formation during tumor progression seems to be closely related to endothelial cells (EC)-mediated angiogenesis. Bone marrow (BM)-derived circulating progenitors including mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and hematopoietic precursor cells (HPCs) also contribute to this process [14,15,16]. However, therapeutic target molecules that effectively inhibit tumor angiogenesis by modulat- ing stem/progenitor cells remain to be identified. In the present study, we hypothesize that phloroglucinol is a good candidate anti-cancer biomolecule that modulates tumor growth during tumor progression by inhibiting the bioactivities of EPCs. Indeed, we demonstrated phloroglucinol’s inhibitory effect on the cell migration, and capillary-like tube formation of EPCs using an in vitro functional assay. Importantly, orally treatment with phloroglucinol effectively disrupted vascular endothelial growth factor (VEGF)-induced de novo vessel formation in an in PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e33618