Alternative responses of primary tumor cells and glioblastoma cell lines to N,N-bis-(8-hydroxyquinoline-5-yl methyl)-benzyl substituted amines: Cell death versus P53-independent senescence

N,N-bis-(8-hydroxyquinoline-5-y1 methyl)-benzyl substituted amines (HQNBA) represent a new class of compounds showing anti-cancer activity At the chemical level the compounds were shown to react preferentially with thiol radicals which may lead to unfolded cysteine containing proteins and subsequent ER-stress At the molecular level, treatment of U87 cells with this class of derivatives induced an over-expression of stress genes, including P53 and numerous P53 target genes By generating shRNA U87 cell clones impaired in P53 expression we found that P53 mediates neither proliferation arrest of treated U87 cells nor over-expression of potential P53 targets Moreover, we discovered that a representative HQNBA derivative (ILK1486) induces strong but transient senescence in U87 cells in a P53-independent manner We demonstrate that, in contrast to its effect on established glioblastoma cell lines, JLK1486 induces extensive death of primary glioblastoma cells We provide evidence that both caspase 3, and 7 activation, and cathepsin B and D activities account for at least part of this cell death