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Angiogenesis

, Volume 14, Issue 1, pp 1–16 | Cite as

SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo

  • Wan-Ru Chao
  • Khalid Amin
  • Yihui Shi
  • Peter Hobbs
  • Mas Tanabe
  • Mary Tanga
  • Ling Jong
  • Nathan Collins
  • Richard Peters
  • Keith Laderoute
  • Dominic Dinh
  • Dawn Yean
  • Carol Hou
  • Barbara Sato
  • Carsten Alt
  • Lidia Sambucetti
Original Paper

Abstract

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -β (ER-β) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 μg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 μM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.

Keywords

Angiogenesis Chick chorioallantoic membrane Fibrin Z-chamber model Hypoxia inducible factor-1α Signal transducer and activator of transcription 3 Tube formation Tumor xenograft Vascular endothelial growth factor 

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Wan-Ru Chao
    • 1
  • Khalid Amin
    • 2
  • Yihui Shi
    • 1
  • Peter Hobbs
    • 1
  • Mas Tanabe
    • 1
  • Mary Tanga
    • 1
  • Ling Jong
    • 1
  • Nathan Collins
    • 1
  • Richard Peters
    • 1
  • Keith Laderoute
    • 1
  • Dominic Dinh
    • 1
  • Dawn Yean
    • 3
  • Carol Hou
    • 1
  • Barbara Sato
    • 1
  • Carsten Alt
    • 1
  • Lidia Sambucetti
    • 1
  1. 1.Drug Discovery Department, Biosciences DivisionSRI InternationalMenlo ParkUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Applied StemCell, Inc.SunnyvaleUSA

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