The mechanism of Zinc chelator bis(DMAS)-QOH to specifically affects p53-mediated transcription-independent apoptotic pathway

There are two p53-mediated apoptotic pathways which are transcription-independent pathway and transcription-dependent pathway. Transcription-dependent pathway is activated by the transcription of p53-targeted factor such as PUMA and Noxa. Transcription-independent pathway is activated by a direct interaction between accumulated p53 and mitochondrial Bcl-2 family members, including Bcl-2, Bcl-xL. However, the contribution ratio of both pathways in the cells and organs is not clear. To clarify the contribution degree to either pathway, it is essential to develop a compound which specifically inhibits either pathway. It is reported that p53 inhibitor pifithrin-µ (PFTµ) specifically suppresses transcription-independent pathway out of two p53-mediated apoptosis pathways and protects mice from bone marrow lethal dose irradiation. However our studies demonstrated that PFTµ cannot protect mice from total-body irradiation, which suggested that it is not a useful tool to examine whether the inhibition of transcription-independent pathway is important to radiation protection. A part of Zinc chelator acts with zinc ion coordinated to p53 DNA binding domain, and inactivates p53, resulting to inhibition of apoptosis. We found 5,7-bis(N,N-dimethylaminosulfonyl)-8-quinolinol (bis(DMAS)-QOH) as the zinc chelator which suppresses the transcription-independent pathway without effecting p53 target-gene expression. Moreover we showed that bis(DMAS)-QOH has lower toxicity and higher cell death inhibitory effect than PFTµ. These results indicate that bis(DMAS)-QOH can be a inhibitor of transcription-independence pathway superior to PFTµ and will be a useful tool to reveal the role of the divergence pathway. We intend to examine the radioprotective effect of bis(DMAS)-QOH in a mouse model and reveal the mechanism for the specificity of it to the transcription-independent pathway.