A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP+-induced apoptosis in human neuroblastoma SH-SY5Y cells

Bioorg Chem. 2017 Jun:72:64-73. doi: 10.1016/j.bioorg.2017.03.011. Epub 2017 Mar 30.

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is a conserved serine/threonine kinase, which regulate transcription, cell differentiation, proliferation and apoptosis. Previous evidences indicated that HIPK2 could be involved in the pathogenesis of neurodegenerative diseases, suggesting as a novel target for Parkinson's disease (PD) therapeutic development. Herein, gene microarray analysis was performed to verify the key regulatory function of HIPK2 in PD. (Z)-methylp-hydroxycinnamate (ZMHC, 7) with other eighteen compounds were isolated from Cannabis sativa subsp. sativa, growing in Bama Yao Autonomous County, one of the five largest longevity regions of the world. Intriguingly, ZMHC was identified to bind HIPK2 with high affinity through molecular modeling and molecular dynamics (MD) simulations. Moreover, cell morphology, flow cytometry and western blot assay suggested that ZMHC inhibited HIPK2, which attenuated MPP+-induced apoptosis in SH-SY5Y cells. In conclusion, these findings discovered a natural product that inhibited HIPK2, and highlighted that ZMHC could be a potential precursor agent for future PD therapy.

Keywords: (Z)-methylp-hydroxycinnamate; Apoptosis; Cannabis sativa subsp. sativa; Homeodomain-interacting protein kinase 2; Parkinson’s disease; SH-SY5Y cells.

MeSH terms

  • Apoptosis / drug effects
  • Biological Products / chemistry
  • Biological Products / isolation & purification
  • Biological Products / pharmacology*
  • Cannabis / chemistry*
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cinnamates / chemistry
  • Cinnamates / isolation & purification
  • Cinnamates / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Models, Molecular
  • Molecular Structure
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Biological Products
  • Carrier Proteins
  • Cinnamates
  • Protein Kinase Inhibitors
  • HIPK2 protein, human
  • Protein Serine-Threonine Kinases