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

2017; Impact Journals LLC; Volume: 8; Issue: 54 Linguagem: Inglês

10.18632/oncotarget.21307

1949-2553

Nara Tae, Trần Mạnh Hưng, Okwha Kim, Nam‐Ho Kim, Su-Hyun Lee, Sunghun Na, Byung Sun Min, Jeong‐Hyung Lee,

Bioactive Natural Diterpenoids Research

Nara Tae 1 , Tran Manh Hung 2, 4 , Okwha Kim 1 , Namho Kim 1 , Suhyun Lee 1 , Sunghun Na 3 , Byung-Sun Min 2 and Jeong-Hyung Lee 1 1 Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea 2 College of Pharmacy, Catholic University of Daegu, Daegu, Republic of Korea 3 Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, Republic of Korea 4 Current/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: bsmin@cu.ac.kr Jeong-Hyung Lee, email: jhlee36@kangwon.ac.kr Keywords: angiogenesis, cassaine diterpene alkaloid, VEGF, eNOS, HSP90 Received: April 15, 2017 Accepted: August 26, 2017 Published: September 28, 2017 ABSTRACT 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.