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Open Access 01-06-2013 | PRECLINICAL STUDIES

A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production

Authors: Durvanei Augusto Maria, Jean Gabriel de Souza, Katia L. P. Morais, Carolina Maria Berra, Hamilton de Campos Zampolli, Marilene Demasi, Simone Michaela Simons, Renata de Freitas Saito, Roger Chammas, Ana Marisa Chudzinski-Tavassi

Published in: Investigational New Drugs | Issue 3/2013

Summary

In cancer-treatment, potentially therapeutic drugs trigger their effects through apoptotic mechanisms. Generally, cell response is manifested by Bcl-2 family protein regulation, the impairment of mitochondrial functions, and ROS production. Notwithstanding, several drugs operate through proteasome inhibition, which, by inducing the accumulation and aggregation of misfolded or unfolded proteins, can lead to endoplasmic reticulum (ER) stress. Accordingly, it was shown that Amblyomin-X, a Kunitz-type inhibitor identified in the transcriptome of the Amblyomma cajennense tick by ESTs sequence analysis of a cDNA library, obtained in recombinant protein form, induces apoptosis in murine renal adenocarcinoma (RENCA) cells by: inducing imbalance between pro- and anti-apoptotic Bcl-2 family proteins, dysfunction/mitochondrial damage, production of reactive oxygen species (ROS), caspase cascade activation, and proteasome inhibition, all ER-stress inductive. Moreover, there was no manifest action on normal mouse-fibroblast cells (NHI3T3), suggesting an Amblyomin-X tumor-cell selectivity. Taken together, these evidences indicate that Amblyomin-X could be a promising candidate for cancer therapy.

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Title: A novel proteasome inhibitor acting in mitochondrial dysfunction, ER stress and ROS production
Authors: Durvanei Augusto Maria
Jean Gabriel de Souza
Katia L. P. Morais
Carolina Maria Berra
Hamilton de Campos Zampolli
Marilene Demasi
Simone Michaela Simons
Renata de Freitas Saito
Roger Chammas
Ana Marisa Chudzinski-Tavassi
Publication date: 01-06-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-012-9871-1

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