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PX-478 2HCl, also called PX-478, is an experimental HIF-1α inhibitor. It inhibited HIF-1α protein at multiple levels in cancer cell lines under normoxia and hypoxia with an IC50 value of ~20-30 μM [1].

Hypoxia-inducible transcription factor HIF-1α activates target genes involved in glycolysis, erythropoiesis and angiogenesis. HIF-1α also regulates the expression of genes coding for apoptotic pathway, growth factors/receptors, cell cycle regulators, metastasis and invasiveness [1].

Under normoxic condition, the IC50 for PX-478 to inhibit HIF-1α in PC3 cells was 20-25 μmol/L, whereas the IC50 for PX-478 to inhibit HIF-1α in the DU 145 cells was ~40-50 μmol/L. in both DU 145 and PC3 cells, 1-hr hypoxia significantly upregulated HIF-1α protein. But the pretreatment with PX-478 for 20 hr under normoxia before 1-hr hypoxia attenuated the accumulation of HIF-1α induced by the 1-hr hypoxia. In PC3 cells, pretreatment with 20 μmol/L PX-478 before hypoxia inhibited HIF-1α by 40% compared to treatment with hypoxia alone. In DU 145 cells, pretreatment with 50 μmol/L PX-478 before hypoxia inhibited HIF-1α by 35% compared to treatment with hypoxia alone [1].

In nu/nu mice with C6 reporter xenografts, treatment with PX-478 at a dose of 30 mg/kg p.o. for 2 consecutive days prevented the transcriptional activity of HIF-1 in central ischemic regions of C6 tumors [2].

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