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p-nitro-Pifithrin-α, a cell-permeable cyclic analog of pifithrin-α, is an inhibitor of p53 activity [1].
The p53 tumor suppressor gene product can induce apoptotic cell death and plays a dominant role in apoptosis, genomic stability, and inhibition of angiogenesis. The p53 has been considered to be an oncogene and the wild-type gene product actually functions as a tumour suppressor gene. p53 mutations play an important role in the development of many common human malignancies [2].
In Vitro: In p53-/- cortical neuron, p-nitro-Pifithrin-α exihibited a p53 inhibitory activity in preventing p53-induced death[1]. p-nitro-Pifithrin-α did not prevent cortical neuronal death induced by p40Met, showing the remarkable specificity in the inhibitory action of p-nitro-Pifithrin-α on p53. p-nitro-Pifithrin-α (300 nM) prevented p53-triggered increase in protein levels of p21/WAF1, indicating that p-nitro-Pifithrin-α behaved as p53 posttranscriptional activity inhibitors. p-nitro-Pifithrin-α at a dose of 30 nM was sufficient to prevent the increase of p21/WAF1 levels [1]. p-nitro-Pifithrin-α was slowly converted into a more potent cyclized form, p-nitro cyclic pifithrin-α, when incubated in biological media (t1/2= 8 h)
In human proximal tubular cells, p-nitro-Pifithrin-α (10 μM) suppressed p53-mediated TGF-β1 expression [3].
In vivo: In a mouse model of non-alcoholic fatty liver disease, p-nitro-Pifithrin-α attenuated steatosis and liver injury in mice fed a high-fat diet [4].
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