Rosuvastatin, Identified From a Zebrafish Chemical Genetic Screen for Antiangiogenic Compounds, Suppresses the Growth of Prostate Cancer

Wang, Chunyang; Tao, Weiyang; Wang, Youdong; Bikow, Jennifer; Lu, Bingxin; Keating, Armand; Verma, Subodh; Parker, Thomas G.; Han, Rong; Wen, Xiao‐Yan

doi:10.1016/j.eururo.2010.05.024

Cited by 116 publications

(93 citation statements)

References 30 publications

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“…On the contrary, statin use was found to be associated with a reduced risk of prostate (40) and colorectal cancer (41). Statins have recently been found to inhibit HUVEC proliferation (16), spheroid sprouting (19) and intersegmental vessel growth in zebrafish embryos (29). In contrast to angiogenesis, the effect of statins on lymphangiogenesis and lymphangiogenic sprouting had not been investigated yet.…”

Section: Discussionmentioning

confidence: 99%

“…There have been previous in vivo phenotypic screens for inhibitors of blood vascular angiogenesis in zebrafish (29,30) and Xenopus tadpoles (31); the latter also investigated the initial embryonic development of the lymphatic system. While such in vivo screening systems integrate all physiological processes and the completeness of a whole organism, they have some potential disadvantages compared to reductionist in vitro screens.…”

Section: Discussionmentioning

confidence: 99%

“…Third, these vertebrate model systems are evolutionary distinct from human, and pharmacological responses sometimes differ tremendously between species as close as mammals; e.g., cytochrome P450 metabolism (35). Fourth, most phenotypic readouts in whole animal screens still depend on visual inspection (29,31), thereby limiting throughput and introducing a potential bias. The two replicate screenings of the ðLOPACÞ 1280 for inhibitors of lymphangiogenic sprouting yielded a top hit rate of 2.4%, identifying 31 compounds with inhibition of at least 20% in both replicates.…”

Section: Discussionmentioning

confidence: 99%

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Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

Schulz

Reisen

Zgraggen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Lymphangiogenesis plays an important role in promoting cancer metastasis to sentinel lymph nodes and beyond and also promotes organ transplant rejection. We used human lymphatic endothelial cells to establish a reliable three-dimensional lymphangiogenic sprouting assay with automated image acquisition and analysis for inhibitor screening. This high-content phenotype-based assay quantifies sprouts by automated fluorescence microscopy and newly developed analysis software. We identified signaling pathways involved in lymphangiogenic sprouting by screening the Library of Pharmacologically Active Compounds ðLOPACÞ 1280 collection of pharmacologically relevant compounds. Hit characterization revealed that mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors substantially block lymphangiogenesis in vitro and in vivo. Importantly, the drug class of statins, for the first time, emerged as potent inhibitors of lymphangiogenic sprouting in vitro and of corneal and cutaneous lymphangiogenesis in vivo. This effect was mediated by inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and subsequently the isoprenylation of Rac1. Supplementation with the enzymatic products of HMG-CoA reductase functionally rescued lymphangiogenic sprouting and the recruitment of Rac1 to the plasma membrane.high-content screening | small compound screening | lymphatic endothelium | chemical genetics

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

Schulz

Reisen

Zgraggen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…From here, the lymphangioblasts migrate toward and then along the arterial intersegmental blood vessels (ISV) to form the thoracic duct by 120 hpf (21). Although small-molecule drug screens using zebrafish embryos have been used to successfully identify inhibitors of mammalian blood vessel development (22)(23)(24), no antilymphatic screens have been reported to date.…”

Section: Introductionmentioning

confidence: 99%

An In Vivo Antilymphatic Screen in Zebrafish Identifies Novel Inhibitors of Mammalian Lymphangiogenesis and Lymphatic-Mediated Metastasis

Astin

Jamieson

Eng

et al. 2014

Molecular Cancer Therapeutics

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The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumorassociated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context. Mol Cancer Ther; 13(10); 2450-62. Ó2014 AACR.

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“…Furthermore, they present powerful imaging solutions through in-vivo fluorescent labeling of desired organs, such as the vasculature system. Several successful screens have been performed in zebrafish, including two screens directed at compound inhibitors of angiogenesis (Tran et al, 2007;Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish

Camus

Quevedo²,

Menéndez

et al. 2011

Oncogene

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Angiogenesis is essential for development and tumor progression. With the aim of identifying new compound inhibitors of the angiogenesis process, we used an established enhanced green fluorescent protein-transgenic zebrafish line to develop an automated assay that enables high-throughput screening of compound libraries in a whole-organism setting. Using this system, we have identified novel kinase inhibitor compounds that show anti-angiogenic properties in both zebrafish in-vivo system and in human endothelial cell in-vitro angiogenesis models. Furthermore, we have determined the kinase target of these compounds and have identified and validated a previously uncharacterized involvement of phosphorylase kinase subunit G1 (PhKG1) in angiogenesis in vivo. In addition, we have found that PhKG1 is upregulated in human tumor samples and that aberrations in gene copy number of PhK subunits are a common feature of human tumors. Our results provide a novel insight into the angiogenesis process, as well as identify new potential targets for anti-angiogenic therapies.

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Rosuvastatin, Identified From a Zebrafish Chemical Genetic Screen for Antiangiogenic Compounds, Suppresses the Growth of Prostate Cancer

Cited by 116 publications

References 30 publications

Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

An In Vivo Antilymphatic Screen in Zebrafish Identifies Novel Inhibitors of Mammalian Lymphangiogenesis and Lymphatic-Mediated Metastasis

Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish

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