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

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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.

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Authors and Affiliations

  1. Drug Discovery Department, Biosciences Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025, USA

    Wan-Ru Chao, Yihui Shi, Peter Hobbs, Mas Tanabe, Mary Tanga, Ling Jong, Nathan Collins, Richard Peters, Keith Laderoute, Dominic Dinh, Carol Hou, Barbara Sato, Carsten Alt & Lidia Sambucetti

  2. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    Khalid Amin

  3. Applied StemCell, Inc., 675 Almanor Ave, Sunnyvale, CA, 94085, USA

    Dawn Yean

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  1. Wan-Ru Chao
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  2. Khalid Amin
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  3. Yihui Shi
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Correspondence to Lidia Sambucetti.

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Chao, WR., Amin, K., Shi, Y. et al. SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo. Angiogenesis 14, 1–16 (2011). https://doi.org/10.1007/s10456-010-9191-z

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