title: SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo.
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.
authors.affiliation: Drug Discovery Department, Biosciences Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA. wan-ru.chao@sri.com
authors.forename: Wan-Ru
authors.initials: WR
authors.lastname: Chao
authors.forename: Khalid
authors.initials: K
authors.lastname: Amin
authors.forename: Yihui
authors.initials: Y
authors.lastname: Shi
authors.forename: Peter
authors.initials: P
authors.lastname: Hobbs
authors.forename: Mas
authors.initials: M
authors.lastname: Tanabe
authors.forename: Mary
authors.initials: M
authors.lastname: Tanga
authors.forename: Ling
authors.initials: L
authors.lastname: Jong
authors.forename: Nathan
authors.initials: N
authors.lastname: Collins
authors.forename: Richard
authors.initials: R
authors.lastname: Peters
authors.forename: Keith
authors.initials: K
authors.lastname: Laderoute
authors.forename: Dominic
authors.initials: D
authors.lastname: Dinh
authors.forename: Dawn
authors.initials: D
authors.lastname: Yean
authors.forename: Carol
authors.initials: C
authors.lastname: Hou
authors.forename: Barbara
authors.initials: B
authors.lastname: Sato
authors.forename: Carsten
authors.initials: C
authors.lastname: Alt
authors.forename: Lidia
authors.initials: L
authors.lastname: Sambucetti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000166:cytology; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C551406:21-(2-(N,N-dimethylamino)ethyl)oxy-7a-methyl-19-norpregna-1,3,5(10),17(20)-tetraen-3-ol; D020533:Angiogenesis Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050796:STAT3 Transcription Factor; D013256:Steroids; D004958:Estradiol; D005337:Fibrin