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-yl 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 (JLK1486) 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.
CNRS, IBDML-UMR-6216, Campus de Luminy Case 907, 13288 Marseille cedex 09, France.
Jean-Louis
JL
Kraus
Filippo
F
Conti
Sébastien
S
Madonna
Aurelie
A
Tchoghandjian
Christophe
C
Beclin
D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000588:Amines; D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D006912:Hydroxyquinolines; C556087:JLK 1486; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D016159:Tumor Suppressor Protein p53