Description
Pifithrin-α (PFT-α; ) is a reversible inhibitor of p53-dependent transcription and apoptosis. Cyclic PFT-α, also known as PFT-β, is a stable analog of PFT-α, formed by the condensation of pifithrin-α in solution. It inhibits the growth of the cancer cell lines IGROV-1, A2780, and HCT116 (IC50 = 23, 77, and 103 μM, respectively). At doses lower than those that inhibit growth, cyclic PFT-α induces autophagy in HCT116 cells and sensitizes IGROV-1 and H460 cells to anti-microtubule agents. In addition, 10 μM cyclic PFT-α blocks p53-dependent protection from DNA damage, induced by hydrogen peroxide or ultraviolet radiation, in melanocytes.
Uses
Cyclic Pifithrin-α hydrobromide has been used as p53 inhibitor to study its role in cigarette smoke?induced apoptosis of pulmonary endothelial cells.
Biochem/physiol Actions
A stable analog of Pifithrin-α (Product Code P4359) with similar biological activities and lower cellular toxicity.
in vitro
pifithrin-α blocks p53-dependent transactivation of p53-responsive genes in cona cells. pifithrin-α (10 μm) inhibits apoptotic death of c8 cells guided by etoposide, taxol, dox, cytosine arabinoside. pifithrin-α has significant effect on the inhibition of p53-dependent growth arrest of human diploid fibroblasts in response to dna damage but not on p53-deficient fibroblasts. pifithrin-α may monitor the nuclear import or export (or both) of p53 or may make nuclear p53 instability [2].
in vivo
pifithrin-α-mice (2.2 mg/kg i.p.) were completely survival with both strains from 60% killing doses of gamma irradiation (8 gy for c57bl and 6 gy for balb/c). mice pretreated with pfithrin-α lost less weight than irradiated mice without the pifithrin-α. pifithrin-α (2.2 mg/kg) eliminates p53-dependent regulation of dna replication after whole-body gamma irradiation in mice [2].
References
[1] komarova ea and gudkov a v. could p53 be a target for therapeutic suppression semin. cancer biol. 1998, 8: 389-400.
[2] komarov pg, komarova ea, kondratov rv, christov-tselkov k, coon js, chernov mv, gudkov av. a chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. science. 1999 sep 10; 285(5434):1733-7.
