title: Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma.
abstract: OBJECTIVE
  SF1126 is a vascular-targeted pan-PI-3K inhibitor prodrug with antitumor and antiangiogenic activity and has completed phase I clinical trial in solid tumors and B-cell malignancies. In this study, we investigated the effect of SF1126 on hypoxic HIF-1α/HIF-2α stability as well as on antitumor and/or antiangiogenic activity in renal cell carcinoma (RCC) models in vitro and in vivo.
  
  
  METHODS
  The effect of SF1126 on hypoxic HIF-1α/HIF-2α protein stability, antitumor and antiangiogenic activity was studied on VHL-null (786-0) and VHL-WT (Caki) RCC cells.
  
  
  RESULTS
  Our data demonstrate that SF1126 treatment abrogates the stabilization of HIF-2α in 786-0 (VHL-mutated) RCC cell line under normoxic and hypoxic conditions. Similarly, hypoxic stabilization of HIF-1α and its activity were also suppressed following SF1126 treatment in Caki cell line (VHL-WT). Herein, we provide mechanistic evidence that HIF-2α can be degraded in cytoplasm under hypoxic conditions via the 26S proteasome and that MDM2 is the E3 ligase which induces the hypoxic degradation of HIF-2α in PI-3K-dependent manner in VHL-deficient RCC cells. Moreover, SF1126 administered to RCC-xenografted mice at 25 mg/kg/dose subcutaneously three times per week for 3 weeks results in marked inhibition of tumor growth (>90 % inhibition) (P < 0.05). Consistent with SF1126 treatment's effects on HIF-1α/HIF-2α, microvessel density analysis of Caki and 786-0 tumor tissues demonstrated that SF1126 has potent antiangiogenic activity in vivo. Finally, SF1126 caused a profound inhibition of integrin-mediated migration and blocked the integrin-induced conversion of GDP-Rac1 to its GTP-bound active state.
  
  
  CONCLUSIONS
  These results validate the in vivo efficacy of SF1126 as a clinically viable antiangiogenic, pan-PI-3K inhibitor prodrug for phase II clinical trials in the treatment of RCC.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology-Oncology, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, 92093-0819, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.forename: Alok R
authors.initials: AR
authors.lastname: Singh
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002867:Chromones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; C526549:SF 1126; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human