Organoseleno cytostatic derivatives: Autophagic cell death with AMPK and JNK activation.

Autor: Garnica P; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Tecnología y Química Farmacéuticas, Campus Universitario, 31080, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008, Pamplona, Spain., Encío I; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008, Pamplona, Spain; Department of Health Sciences, Public University of Navarra, Avda. Barañain s/n, E-31008, Pamplona, Spain., Plano D; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Tecnología y Química Farmacéuticas, Campus Universitario, 31080, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008, Pamplona, Spain., Palop JA; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Tecnología y Química Farmacéuticas, Campus Universitario, 31080, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008, Pamplona, Spain., Sanmartín C; Universidad de Navarra, Facultad de Farmacia y Nutrición, Departamento de Tecnología y Química Farmacéuticas, Campus Universitario, 31080, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008, Pamplona, Spain. Electronic address: sanmartin@unav.es.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 Aug 01; Vol. 175, pp. 234-246. Date of Electronic Publication: 2019 May 04.
DOI: 10.1016/j.ejmech.2019.04.074
Abstrakt: Selenocyanates and diselenides are potential antitumor agents. Here we report two series of selenium derivatives related to selenocyanates and diselenides containing carboxylic, amide and imide moieties. These compounds were screened for their potency and selectivity against seven tumor cell lines and two non-malignant cell lines. Results showed that MCF-7 cells were especially sensitive to the treatment, with seven compounds presenting GI 50 values below 10 μM. Notably, the carboxylic selenocyanate 8b and the cyclic imide 10a also displayed high selectivity for tumor cells. Treatment of MCF-7 cells with these compounds resulted in cell cycle arrest at S phase, increased levels of pJNK and pAMPK and caspase independent cell death. Autophagy inhibitors wortmannin and chloroquine partially prevented 8b and 10a induced cell death. Consistent with autophagy, increased Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels were detected. Our results point to 8b and 10a as autophagic cell death inducers.
(Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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