Evaluation of Zinc (II) chelators for inhibiting p53-mediated apoptosis

Akinori Morita, Shinya Ariyasu, Soichiro Ohya, Ippei Takahashi, Bing Wang, Kaoru Tanaka, Takatoshi Uchida, Haruna Okazaki, Kengo Hanaya, Atsushi Enomoto, Mitsuru Nenoi, Masahiko Ikekita, Shin Aoki, Yoshio Hosoi

研究成果: Article査読

17 被引用数 (Scopus)

抄録

In a previous study, we reported that sodium orthovanadate (vanadate) is the first known inhibitor that is capable of protecting mice from death from the radiation-induced gastrointestinal syndrome via its ability to block both transcription-dependent and transcription-independent p53 apoptotic pathways. In this paper, we report that vanadate has a unique activity for inducing the denaturation of p53 relative to other known radioprotective p53 inhibitors, pifithrin-α (PFTα) and pifithrin-μ (PFTμ). This potent radioprotective effect of vanadate prompted us to undertake a more extensive search for p53 inhibitors that can induce p53 denaturation. Based on the fact that p53 denaturation can be induced by the dissociation of a zinc ion, which is used as a structural factor of p53, we screened some zinc (II) chelators for the suppression of the DNA binding activity of p53 in vitro and the inhibition of radiation-induced p53-dependent apoptosis in MOLT-4 cells. The findings indicate that two of five zinc (II) chelators also suppressed apoptosis. Among the inhibitors tested, Bispicen (N,N'-Bis(2-pyridylmethyl)-1,2-ethanediamine) had the highest inhibition activity. A mechanistic study using cells bearing different p53 status or functions (i.e., p53-knockdown MOLT-4 transformant and its revertants, p53 mutant cells, p53-null cells), and p53-independent apoptotic stimuli revealed that the suppressive effect of Bispicen on apoptosis is specifically mediated through p53. Moreover, Bispicen, similar to vanadate, induces the denaturation of p53 as well as the blocking of both transcription-dependent and -independent apoptotic pathways. Our findings indicate that the use of zinc (II) chelators represent a new approach for protecting against radiation-induced p53-dependent apoptosis through the inhibition of p53-dependent apoptotic pathways.

本文言語English
ページ(範囲)2439-2450
ページ数12
ジャーナルOncotarget
4
12
DOI
出版ステータスPublished - 2013 12
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学

フィンガープリント

「Evaluation of Zinc (II) chelators for inhibiting p53-mediated apoptosis」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル