Open AccessA diphenyldiselenide derivative induces autophagy via JNK in HTB‐54 lung cancer cells
Author(s) -
Díaz Marta,
González Roncesvalles,
Plano Daniel,
Palop Juan Antonio,
Sanmartín Carmen,
Encío Ignacio
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13318
Subject(s) - apoptosis , autophagy , programmed cell death , cytotoxicity , cytotoxic t cell , chemistry , cancer cell , cancer research , kinase , cell culture , caspase , cell cycle checkpoint , cell cycle , cancer , biology , in vitro , biochemistry , genetics
Abstract 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.