Garcimultiflorone K inhibits angiogenesis through Akt/eNOS- and mTOR-dependent pathways in human endothelial progenitor cells

Chen-Yu Yang; Chi Chen; Cheng-Yung Lin; Yi-Hsuan Chen; Chih-Yang Lin; Chih-Wen Chi; Yu-Jen Chen; Shih-Chia Liu; Ting-Kuo Chang; Chih-Hsin Tang; Yu-Wei Lai; Huai-Jen Tsai; Jih-Jung Chen; Shih-Wei Wang

doi:10.1016/j.phymed.2019.152911

Garcimultiflorone K inhibits angiogenesis through Akt/eNOS- and mTOR-dependent pathways in human endothelial progenitor cells

Phytomedicine. 2019 Nov:64:152911. doi: 10.1016/j.phymed.2019.152911. Epub 2019 Apr 2.

Authors

Chen-Yu Yang¹, Chi Chen², Cheng-Yung Lin³, Yi-Hsuan Chen², Chih-Yang Lin², Chih-Wen Chi⁴, Yu-Jen Chen⁵, Shih-Chia Liu¹, Ting-Kuo Chang⁶, Chih-Hsin Tang⁷, Yu-Wei Lai⁸, Huai-Jen Tsai³, Jih-Jung Chen⁹, Shih-Wei Wang¹⁰

Affiliations

¹ Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan.
² Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan.
³ Institute of Biomedical Sciences, Mackay Medical College, New Taipei City, Taiwan.
⁴ Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan.
⁵ Department of Medical Research, MacKay Memorial Hospital, New Taipei City, Taiwan; Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan.
⁶ Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan.
⁷ Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan; Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
⁸ Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan; Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
⁹ Faculty of Pharmacy, School of Pharmaceutical Sciences, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: chenjj@ym.edu.tw.
¹⁰ Department of Medicine, Mackay Medical College, No. 46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: shihwei@mmc.edu.tw.

PMID: 31454653
DOI: 10.1016/j.phymed.2019.152911

Abstract

Background Garcimultiflorone K is a novel polyprenylated polycyclic acylphloroglucinol isolated from the stems of Garcinia multiflora that exhibits promising anti-angiogenic activity in human endothelial progenitor cells (EPCs). Purpose This study sought to determine the underlying anti-angiogenic mechanisms and pharmacological properties of garcimultiflorone K. Methods We examined the anti-angiogenic effects of garcimultiflorone K and its mechanisms of action using in vitro EPC models and in vivo zebrafish embryos. Results EPCs proliferation, migration, differentiation and capillary-like tube formation were effectively and concentration-dependently inhibited by garcimultiflorone K without any signs of cytotoxicity. Our investigations revealed that garcimultiflorone K suppressed EPCs angiogenesis through Akt, mTOR, p70S6K, and eNOS signaling cascades. Notably, garcimultiflorone K dose-dependently impeded angiogenesis in zebrafish embryos. Conclusion Our data demonstrate the anti-angiogneic effects of garcimultiflorone K in both in vitro and in vivo models. Garcimultiflorone K appears to have potential in the treatment of angiogenesis-related diseases.

Keywords: Angiogenesis; Garcimultiflorone K; Signaling pathway.

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Endothelial Progenitor Cells / drug effects
Garcinia / chemistry*
Humans
Neovascularization, Pathologic / drug therapy*
Nitric Oxide Synthase Type III / metabolism
Phloroglucinol / chemistry
Phloroglucinol / pharmacology*
Proto-Oncogene Proteins c-akt / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / drug effects*
TOR Serine-Threonine Kinases / metabolism
Zebrafish

Substances

Angiogenesis Inhibitors
garcimultiflorone K
Phloroglucinol
NOS3 protein, human
Nitric Oxide Synthase Type III
MTOR protein, human
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
TOR Serine-Threonine Kinases