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Title: Inhibitory effects of local anesthetics on the proteasome and their biological actions
Authors: Bahrudin, Udin
Unno, Masaki
Nishio, Kazuya
Kita, Akiko  kyouindb  KAKEN_id
Li, Peili
Kato, Masaru
Inoue, Masashi
Tsujitani, Shunichi
Murakami, Takuto
Sugiyama, Rina
Saeki, Yasushi
Obara, Yuji
Tanaka, Keiji
Yamaguchi, Hiroshi
Sakane, Isao
Kawata, Yasushi
Itoh, Toshiyuki
Ninomiya, Haruaki
Hisatome, Ichiro
Morimoto, Yukio  kyouindb  KAKEN_id  orcid (unconfirmed)
Author's alias: 西尾, 和也
喜田, 昭子
森本, 幸生
Keywords: Drug development
Molecular modelling
Issue Date: 11-Jul-2017
Publisher: Springer Nature
Journal title: Scientific Reports
Volume: 7
Thesis number: 5079
Abstract: Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells.
Rights: © The Author(s) 2017.
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
DOI(Published Version): 10.1038/s41598-017-04652-2
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