PX-478

PX-478 is a multifunctional HIF-1α inhibitor with properties including radiosensitization, autophagy activation, and lipid accumulation inhibition. PX-478 also blocks hypoxia-induced VEGF production and regulates β-cell phenotypes under hypoxic conditions. PX-478 induces cell cycle arrest and DNA damage, restores autophagic function, reduces foam cell formation, and maintains glucose homeostasis. PX-478 is widely used in research on related diseases such as human tumors (e.g., prostate cancer), type 2 diabetes, and atherosclerosis^[1][2][3][4]. In Vitro:PX-478 (25 μM; 16 h) inhibits HIF-1α translation in human breast cancer MCF-7 cells under both normoxic and hypoxic conditions, with a more pronounced effect under hypoxic conditions; it also reduces global protein synthesis (especially under hypoxic conditions), yet does not alter the phosphorylation levels of hypoxia-induced translation pathway components eIF2α and 4E-BP, and suppresses the reporter gene activity driven by the 5'-UTR of HIF-1α and c-Myc^[1].
PX-478 (20-50 μM; 20 h) inhibits HIF-1α protein in human prostate cancer cell lines PC3 and DU 145. Its activity in PC3 cells (with an IC₅₀ of 20-25 μM under normoxic conditions) is stronger than that in DU 145 cells (with an IC₅₀ of approximately 40-50 μM under normoxic conditions), and it also attenuates hypoxia-induced HIF-1α accumulation in both cell lines^[2].
PX-478 (16-35 μM; 18-20 hr) reduces the clonogenic survival rate of PC3 and DU 145 human prostate cancer cells; PC3 cells show higher sensitivity under normoxic conditions (IC₅₀ 17 μM), while the sensitivity of DU 145 cells increases under hypoxic conditions (IC₅₀ 22 μM)^[2].
PX-478 (15-20 μM; 24 hr) enhances the radiosensitivity of human PC3 prostate cancer cells under normoxic irradiation conditions, with an enhancement factor (EF) of 1.44 at 20 μM (24 hr incubation) and 1.19 at 15 μM (24 hr incubation)^[2].
PX-478 (20-30 μM; 20 hr) enhances the radiosensitivity of hypoxic-irradiated human prostate cancer PC3 cells, with an enhancement factor (EF) of 1.56 at 20 μM (pretreated under normoxic conditions for 20 hours) and 1.78 at 30 μM (pretreated under normoxic conditions for 20 hours)^[2].
Treatment with PX-478 (10-50 μM; 24 hr) induces S/G2M phase arrest in the human prostate cancer cell line PC3, but exerts no significant effect on the cell cycle distribution of the human prostate cancer cell line DU 145^[2].
PX-478 (20 μM; 30 min-18 hr) induces sustained phosphorylation of γH2AX (a marker of DNA double-strand breaks) in human prostate cancer cell lines PC3 and DU 145, and prolongs radiation-induced γH2AX expression in PC3 cells even after only a short (30 min) treatment^[2].
PX-478 improves pancreatic β-cell function in islets of mice with glucose metabolism disorders by inhibiting abnormal low-glucose intracellular Ca²⁺ oscillations and excessive basal insulin release^[3].
PX-478 (100 μM; 48 h) restores autophagic function, inhibits ferroptosis and reduces lipid accumulation in ox-LDL-induced THP-1 macrophage foam cells by downregulating HIF-1α, and these effects depend on intact autophagy^[4]. In Vivo:PX-478 exhibits potent antitumor activity against HIF-1A-expressing human tumor xenografts in vivo in immunodeficient mice, inducing marked tumor regression, prolonged tumor growth delays, and cures in some animals^[1].
PX-478 (free base) exhibits in vivo antitumor activity against human tumor xenografts, with activity positively correlated with tumor HIF-1α levels and primary activity attributed to inhibition of glycolysis via prolonged Glut-1 reduction^[2].
PX-478 (free base) (daily; 5 days) causes neutropenia as the primary acute toxicity in nonimmunodeficient C57BL/6 mice^[2].
PX-478 (free base) prevents glycemia elevation and diabetes progression by sustaining elevated plasma insulin concentrations in db/db mice^[3].
PX-478 (free base) improves glucose homeostasis recovery and enhances multiple markers of pancreatic β cell function and maturity in streptozotocin-induced diabetic mice^[3].
PX-478 (5 mg/kg; i.p.; once every two days; two months) reduces atherosclerotic plaque, lipid lesion, and mucin areas by downregulating HIF-1α expression in HFD-fed ApoE^-/- mice^[4].