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

作者：Diaz Marta; Gonzalez Roncesvalles; Plano Daniel; Antonio Palop Juan; Sanmartin Carmen; Encio Ignacio

来源：JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2018, 22(1): 289-301.

DOI：10.1111/jcmm.13318

<jats:title>Abstract</jats:title><jats:p>Symmetric aromatic diselenides are potential anticancer agents with strong cytotoxic activity. In this study, the <jats:italic>in vitro</jats:italic> 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 <jats:bold>2</jats:bold>, the compound with the lowest mean GI<jats:sub>50</jats:sub> value, induced both caspase‐dependent apoptosis and arrest at the G<jats:sub>0</jats:sub>/G<jats:sub>1</jats:sub> 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 <jats:bold>2</jats:bold> treatment. Mutated p53 expressed in CCRF‐CEM cells retains its transactivating activity. Therefore, increased levels of p21<jats:sup>CIP1</jats:sup> and BAX proteins were also detected. On the other hand, DPDS <jats:bold>6</jats:bold>, the compound with the highest selectivity index for cancer cells, resulted in G<jats:sub>2</jats:sub>/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 <jats:bold>6</jats:bold>‐induced cell death. Consistent with autophagy, increased LC3‐II and decreased SQSTM1/p62 levels were detected in HTB‐54 cells in response to DPDS <jats:bold>6</jats:bold>. 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 <jats:bold>6</jats:bold>‐induced cell death indicating that JNK activation is involved in DPDS <jats:bold>6</jats:bold>‐induced autophagy. These results highlight the anticancer effects of these derivatives and warrant future studies examining their clinical potential.</jats:p>

• 出版日期2018-1