Uses
p-nitro-Cyclic Pifithrin-α is an inactivator of p53 that blocks p53-dependent transcriptional activation and apoptisis. Anti-cancer agent.
General Description
A cell-permeable p53 inhibitor that exhibits 10-fold higher potency (ED
50 = 30 nM in protecting etoposide-induced cortical neuron death) and 50% longer half-life (
t1/2 = 6h in neuron culture medium at 37°C) than Pifithrin-α (Cat. No.
506132). However, despite its
in vitro efficacy, this inhibitor is not effective when adminstered in rats
in vivo. For
in vivo applications, please consider Pifithrin-α,
p-Nitro (Cat. No.
506152).
Biological Activity
p-nitro-cyclic pifithrin-α is an inactivator of p53.the activation of the tumor suppressor gene p53 plays a key role in regulating the in-vitro death of neurons, following apoptotic stimuli molecules including glutamate and dna-damaging agents. thus, p53 inhibitors may prove effective in suppressing the degenerative processes in neurodegenerative disorders.
Biochem/physiol Actions
Cell permeable: yes
in vitro
pifithrin-α (pft-α) was identified as an inactivator of p53 blocking p53-dependent transcriptional activation and apoptosis. cyclic pft-α was a stable analog of pft-α. p-nitro-cyclic pft-α, a cell-permeable form of cyclic pft-α, was found to be one order of magnitude more active than pft-α in protecting cortical neurons exposed to etoposide. p-nitro-cyclic pft-α acted in a p53-dependently but did not block phosphorylation of p53 on ser15 in response to etoposide treatment, although it prevented p53 posttranscriptional activity [1].
in vivo
in a previou study, c57bl/6 mice were fed a high-fat (hfd) or control diet for 8 weeks; pft was administered three times per week. results showed that pft administration could suppress hfd-induced weight gain, steatosis, oxidative stress, alt elevation, and apoptosis. pft treatment also able to blunt the hfd-induced upregulation of mirna34a and increase sirt1 expression. in the livers of hfd-fed, pft-treated mice, activation of the sirt1/pgc1α/pparα axis increased the expression of malonyl-coa decarboxylase [2].
References
[1] . pietrancosta, n.,moumen, a.,dono, r., et al. imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism. journal of medicinal chemistry 49(12), 3645-3652 (2006).
[2] derdak z, villegas ka, harb r, wu am, sousa a, wands jr. inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. j hepatol. 2013 apr;58(4):785-91.
