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

Author(s)

Maria, Durvanei Augusto ^[1] ; de Souza, Jean Gabriel ^{[2, 1]} ; Morais, Katia L. P. ^{[2, 1]} ; Berra, Carolina Maria ^[1] ; Zampolli, Hamilton de Campos ^{[1, 3]} ; Demasi, Marilene ^[1] ; Simons, Simone Michaela ^[1] ; Saito, Renata de Freitas ^[4] ; Chammas, Roger ^[4] ; Chudzinski-Tavassi, Ana Marisa ^{[2, 1, 3]}

Affiliation

^[1] Inst Butantan, Lab Bioquim & Biofis, BR-05503900 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Bioquim, Sao Paulo - Brazil

^[3] Inst Butantan, Programa Posgrad Interunidades Biotecnol, USP, IPT, BR-05503900 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Lab Oncol Expt LIM24, Sao Paulo - Brazil

• Document type: Journal article
• Source: INVESTIGATIONAL NEW DRUGS; v. 31, n. 3, p. 493-505, JUN 2013.
• Web of Science Citations: 25

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. (AU)

• FAPESP's process: 98/14307-9 - Center for Applied Toxinology
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC