Research Papers:

A cassaine diterpene alkaloid, 3β-acetyl-nor-erythrophlamide, suppresses VEGF-induced angiogenesis and tumor growth via inhibiting eNOS activation

Nara Tae, Tran Manh Hung, Okwha Kim, Namho Kim, Suhyun Lee, Sunghun Na, Byung-Sun Min _ and Jeong-Hyung Lee

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Oncotarget. 2017; 8:92346-92358. https://doi.org/10.18632/oncotarget.21307

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Nara Tae1, Tran Manh Hung2,4, Okwha Kim1, Namho Kim1, Suhyun Lee1, Sunghun Na3, Byung-Sun Min2 and Jeong-Hyung Lee1

1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea

2College of Pharmacy, Catholic University of Daegu, Daegu, Republic of Korea

3Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea

4Current/Present address: Biomedical Science Department, VNUK Institute for Research & Executive Education, The University of Da Nang, Da Nang, Vietnam

Correspondence to:

Byung-Sun Min, email: [email protected]

Jeong-Hyung Lee, email: [email protected]

Keywords: angiogenesis, cassaine diterpene alkaloid, VEGF, eNOS, HSP90

Received: April 15, 2017    Accepted: August 26, 2017    Published: September 28, 2017


Angiogenesis is one of the hallmarks of cancer, playing an essential role in tumor growth, invasion, and metastasis. 3β-Acetyl-nor-erythrophlamide (3-ANE), a cassaine diterpene alkaloid compound from Erythrophleum fordii, exerts various pharmacological effects, including antitumor activity. However, the effects of 3-ANE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that 3-ANE inhibited the vascular endothelial growth factor (VEGF)-mediated proliferation, migration, invasion, and capillary-like tube formation of human umbilical vascular endothelial cells (HUVECs), without inducing apoptosis. We also found that 3-ANE blocked angiogenesis in vivo, and suppressed tumor angiogenesis and human lung adenocarcinoma growth in the xenograft tumor model. Furthermore, we showed that 3-ANE blocked VEGF-mediated endothelial nitric oxide synthase (eNOS) phosphorylation, vascular permeability and NO production in HUVECs, via disrupting the VEGF-induced association of eNOS and heat-shock protein 90 (HSP90). Our studies therefore provide the first evidence that 3-ANE inhibits tumor angiogenesis by inhibiting the VEGF-mediated eNOS activation and NO production, and 3-ANE could be a potential candidate in angiogenesis-related disease therapy.

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