Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma.

Abstract

PURPOSE:

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: Shweta Joshi, Alok R Singh, Donald L Durden
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 75 Issue 3 Pg. 595-608 (Mar 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25578041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Chromones
• Hypoxia-Inducible Factor 1, alpha Subunit
• Oligopeptides
• Phosphoinositide-3 Kinase Inhibitors
• Prodrugs
• SF 1126
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Cell Line, Tumor
• Chromones (pharmacology)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects, metabolism)
• Injections, Subcutaneous
• Kidney Neoplasms (drug therapy, pathology)
• Mice
• Mice, Nude
• Oligopeptides (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Prodrugs
• Von Hippel-Lindau Tumor Suppressor Protein (genetics)
• Xenograft Model Antitumor Assays