Major Contribution of Caspase-9 to Honokiol-Induced Apoptotic Insults to Human Drug-Resistant Glioblastoma Cells

Molecules. 2020 Mar 23;25(6):1450. doi: 10.3390/molecules25061450.

Abstract

Temozolomide (TMZ)-induced chemoresistance to human glioblastomas is a critical challenge now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), can kill human glioblastoma cells and suppresses glioblastoma growth. This study was further aimed to evaluate the effects of honokiol on human drug-resistant glioblastoma cells and the possible mechanisms. The results by data mining in the cancer genome atlas (TCGA) database and immunohistochemistry displayed that expression of caspase-9 mRNA and protein in human glioblastomas was induced. Human TMZ-resistant U87-MG-R9 glioblastoma cells were selected and prepared from human drug-sensitive U87-MG cells. Compared to human drug-sensitive U87-MG cells, TMZ did not affect viability of U87-MG-R9 glioblastoma cells. Interestingly, treatment with honokiol suppressed proliferation and survival of human drug-resistant glioblastoma cells in concentration- and time-dependent manners. Compared to caspase-8 activation, honokiol chiefly increased activity of caspase-9 in U87-MG-R9 cells. Successively, levels of cleaved caspase-3 and activities of caspase-3 and caspase-6 in human TMZ-tolerant glioblastoma cells were augmented following honokiol administration. In parallel, honokiol triggered DNA fragmentation of U87-MG-R9 cells. Accordingly, treatment of human TMZ-resistant glioblastoma cells with honokiol induced cell apoptosis but did not affect cell necrosis. Fascinatingly, suppressing caspase-9 activity using its specific inhibitors repressed honokiol-induced caspase-6 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the major roles of caspase-9 in transducing honokiol-induced mitochondria-dependent apoptosis in human drug-resistant glioblastoma cells. Thus, honokiol may be clinically applied as a drug candidate for treatment of glioblastoma patients with chemoresistance.

Keywords: apoptotic insults; caspase-9; drug-resistant glioblastomas; honokiol.

MeSH terms

  • Apoptosis / drug effects*
  • Biphenyl Compounds / pharmacology*
  • Caspase 9 / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Activation / drug effects
  • Glioblastoma* / drug therapy
  • Glioblastoma* / enzymology
  • Glioblastoma* / pathology
  • Humans
  • Lignans / pharmacology*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplasm Proteins / metabolism*
  • Temozolomide / pharmacology

Substances

  • Biphenyl Compounds
  • Lignans
  • Neoplasm Proteins
  • honokiol
  • CASP9 protein, human
  • Caspase 9
  • Temozolomide