Uses

PX 478 is a HIF-1α inhibitor that may be used in cancer therapy for treatment of solid tumors. PX478 has also been shown to suppress high-fat-diet (HFD)-induced HIFα activation in adipose tissue in mice and therefore may be used to ameliorate adipose tissue dysfunction.

Biological Activity

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].

in vivo

References

[1]. palayoor st, mitchell jb, cerna d, et al. px-478, an inhibitor of hypoxia-inducible factor-1α, enhances radiosensitivity of prostate carcinoma cells. international journal of cancer, 2008, 123(10): 2430-2437.
[2]. schwartz dl, powis g, thitai-kumar a, et al. the selective hypoxia inducible factor-1 inhibitor px-478 provides in vivo radiosensitization through tumor stromal effects. molecular cancer therapeutics, 2009, 8(4): 947-958.