A diphenyldiselenide derivative induces autophagy via JNK in HTB-54 lung cancer cells.

Autor: Díaz M; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.; Instituto de Investigaciones Sanitarias de Navarra (IDISNA), Pamplona, Spain., González R; Departamento de Ciencias de la Salud, Universidad Pública de Navarra, Pamplona, Spain., Plano D; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.; Instituto de Investigaciones Sanitarias de Navarra (IDISNA), Pamplona, Spain., Palop JA; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.; Instituto de Investigaciones Sanitarias de Navarra (IDISNA), Pamplona, Spain., Sanmartín C; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.; Instituto de Investigaciones Sanitarias de Navarra (IDISNA), Pamplona, Spain., Encío I; Departamento de Ciencias de la Salud, Universidad Pública de Navarra, Pamplona, Spain.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2018 Jan; Vol. 22 (1), pp. 289-301. Date of Electronic Publication: 2017 Sep 18.
DOI: 10.1111/jcmm.13318
Abstrakt: Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the in vitro anticancer activities of a novel series of diarylseleno derivatives from the diphenyldiselenide (DPDS) scaffold were evaluated. Most of the compounds exhibited high efficacy for inducing cytotoxicity against different human cancer cell lines. DPDS 2, the compound with the lowest mean GI 50 value, induced both caspase-dependent apoptosis and arrest at the G 0 /G 1 phase in acute lymphoblastic leucemia CCRF-CEM cells. Consistent with this, PARP cleavage; enhanced caspase-2, -3, -8 and -9 activity; reduced CDK4 expression and increased levels of p53 were detected in these cells upon DPDS 2 treatment. Mutated p53 expressed in CCRF-CEM cells retains its transactivating activity. Therefore, increased levels of p21 CIP1 and BAX proteins were also detected. On the other hand, DPDS 6, the compound with the highest selectivity index for cancer cells, resulted in G 2 /M cell cycle arrest and caspase-independent cell death in p53 deficient HTB-54 lung cancer cells. Autophagy inhibitors 3-methyladenine, wortmannin and chloroquine inhibited DPDS 6-induced cell death. Consistent with autophagy, increased LC3-II and decreased SQSTM1/p62 levels were detected in HTB-54 cells in response to DPDS 6. Induction of JNK phosphorylation and a reduction in phospho-p38 MAPK were also detected. Moreover, the JNK inhibitor SP600125-protected HTB-54 cells from DPDS 6-induced cell death indicating that JNK activation is involved in DPDS 6-induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential.
(© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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