Mechanism of a zinc chelator acts specifically by inhibiting p53-mediated transcription-independent apoptotic pathway

Recent studies have revealed that there are two branches in p53-mediated apoptotic pathway: one is mediated through transcription of p53 target genes, another is initiated by direct interactions between p53 and mitochondrial Bcl-2 family members, which are so-called respectively “transcription-dependent and transcription-independent pathways.” However, the relative contributions of each in different types of cells and tissues are not yet clearly defined. To clarify the contributions, it is essential to use some chemical inhibitors that could selectively inhibit the different pathways. Pifithrin-μ (PFTμ) is so far the only reported p53 inhibitor specifically suppressing the transcription-independent pathway in the cultured cells. Though it was also reported to protect death from radiation-induced hematopoietic syndrome in mice, our recent study did not demonstrate any reproducibility of such a protective effect. Thus it makes the significance of the transcription-independent pathway in radioprotection be worthy of further verification. Some zinc chelators are known to inhibit p53 by inducing dissociation of a zinc ion from the metal ion binding site of p53. In the present study, 5, 7-bis(N,N-dimethylaminosulfonyl)-8-quinolinol (bis(DMAS)-QOH), a zinc chelator, was found to suppress the transcription-independent pathway without affecting the expression of p53 target genes. Moreover, bis(DMAS)-QOH showed lower toxicity and higher cell death inhibitory effect than PFTμ. These results suggest that bis(DMAS)-QOH can be a superior inhibitor to PFTμ against the transcription-independent pathway to reveal the role of the divergence pathway.