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Sensitization of Hepatocellular Carcinoma Cells to A po2 L / TRAIL by a Novel Akt/ NF ‐κ B Signalling Inhibitor
Author(s) -
Omar Hany A.,
Arafa ElShaimaa A.,
Maghrabi Ibrahim A.,
Weng JingRu
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12190
Subject(s) - apoptosis , survivin , protein kinase b , chemistry , iκbα , tumor necrosis factor alpha , nf κb , cancer research , p50 , phosphorylation , microbiology and biotechnology , biology , immunology , transcription factor , biochemistry , gene
Hepatocellular carcinoma ( HCC ) cells are intrinsically resistant to tumour necrosis factor‐related apoptosis ligand ( A po2 L / TRAIL ), in part, due to the compensatory activation of nuclear factor‐kappa B ( NF ‐κ B ). To broaden the clinical utilization of A po2 L / TRAIL in HCC , OSU ‐ A9 , a potent indole‐3‐carbinol‐derived A kt/ NF ‐κ B signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU ‐ A 9, A po2 L / TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF ‐κ B reporter gene and RT ‐ PCR were tested for the activation of NF ‐κ B and the expression of death receptors ( DR )4 and 5. OSU ‐ A 9 could sensitize HCC cells to A po2 L / TRAIL with high potency through down‐regulation of A kt/ NF ‐κ B signalling. OSU ‐ A 9 dose‐dependently reduced A kt phosphorylation and the expression and nuclear localization of R el A /p65, accompanied by parallel decreases in the expression of NF ‐κ B target products, including B cl‐ xL , M cl‐1, c IAP 1, c IAP 2 and survivin. Moreover, OSU ‐ A 9 increased DR 5 expression through a reactive oxygen species ( ROS )‐dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU‐A9 and A po2 L / TRAIL in mediating apoptotic death in HCC cells. The ability of OSU ‐ A 9 to accentuate A po2 L / TRAIL ‐induced apoptosis by inactivating A kt/ NF ‐κ B signalling might foster a promising therapeutic strategy for HCC .