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

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

Author Maria, Durvanei Augusto Google Scholar
Souza, Jean Gabriel de Autor UNIFESP Google Scholar
Morais, Katia Luciano Pereira Autor UNIFESP Google Scholar
Berra, Carolina Maria Google Scholar
Zampolli, Hamilton de Campos Google Scholar
Demasi, Marilene Google Scholar
Simons, Simone Michaela Google Scholar
Saito, Renata de Freitas Google Scholar
Chammas, Roger Google Scholar
Chudzinski-Tavassi, Ana Marisa Autor UNIFESP Google Scholar
Institution Inst Butantan
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Abstract 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.
Keywords Apoptosis
Bcl-2 family protein
Caspase
Reactive oxygen species
Proteasome
Endoplasmic reticulum stress
Amblyomin-X
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Uniao Quimica Farmaceutica Nacional
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: FAPESP 2010/52669-3
FAPESP: CAT/CEPID - 1998/14307-9
Date 2013-06-01
Published in Investigational New Drugs. Dordrecht: Springer, v. 31, n. 3, p. 493-505, 2013.
ISSN 0167-6997 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 493-505
Origin http://dx.doi.org/10.1007/s10637-012-9871-1
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000318657000001
URI http://repositorio.unifesp.br/handle/11600/36357

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