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AW 464 – Inhibition of HIF signal transduction

0. 3. 0. 2. 0. 1. 0. 0. AW 464 – Inhibition of HIF signal transduction. ● Inhibition of HRE-HIF-1 α DNA binding. Cos 7/CoCl2. MDA468 hypoxia. MDA468 normoxia. MDA468 hypoxia AW464 10  M. MDA468 hypoxia AJM290 10  M. Cos 7/CoCl2+Competitor Oligo 500ng.

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AW 464 – Inhibition of HIF signal transduction

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  1. 0 . 3 0 . 2 0 . 1 0 . 0 AW 464 – Inhibition of HIF signal transduction ● Inhibition of HRE-HIF-1αDNA binding Cos 7/CoCl2 MDA468 hypoxia MDA468 normoxia MDA468 hypoxia AW464 10M MDA468 hypoxia AJM290 10M Cos 7/CoCl2+Competitor Oligo 500ng MDA468 hypoxia +Competitor Oligo 500ng

  2. AW 464 -Inhibition of HIF signal transduction Inhibition of hypoxia-induced gene transactivation: Dose-dependent down-regulation of BNIP3 mRNA by: A) AW 464 B) AJM 290

  3. μM RCC4 + VHL N Hypoxia AJM290 AW464 C C 1 2.5 10 1 2.5 10 (μM) AJM 290 AW 464 CA-IX BNIP3 AW 464 -Inhibition of HIF signal transduction • Dose-dependent down regulation of HIF-mediated signal transduction: CA-IX protein expression: MDA 468 ER- mammary carcinoma cells under hypoxia and normoxia • BNIP3 protein expression: MDA 468 cells under hypoxia and normoxia • RCC4 renal carcinoma cells (mutant VHL) • RCC4 cells + VHL transfectant under normoxia and hypoxia

  4. AW 464 –Anti-angiogenic activity • Dose-dependent inhibition VEGF production AW 464 • Inhibition of human umbilical cord vein endothelial cell proliferation (IC50 500 nM) • Inhibition of endothelial cell differentiation (tubal abortion 500 nM, Matrigel™ model)

  5. Cell Number H2DCFDA fluorescence AW 464 –Modulation of REDOX regulation Modulation of REDOX regulation • Generation of reactive oxygen species (ROS) 1 mM, 3 – 7 h, HCT116 - Leading to induction of apoptosis 1 mM, 12 – 16 h, HCT116 - Enhanced potency (10-fold) following depletion of intracellular GSH

  6. 24hrs 12hrs C 1 3 6 PMX 464 (μM) PARP Cleaved PARP Caspase 3 DMSO AW 46424 h AW 464 –Induction of Apoptosis G2/M block, preG1 population - 1 μM ≥16 h in breast and colon cell lines - Dose-dependent CDK-1 down-regulation 3h Propidium Iodide Cleaved caspase 3 Annexin V-FITC

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