Combined treatment with 2'-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness

J Neurooncol. 2019 May;143(1):69-77. doi: 10.1007/s11060-019-03151-w. Epub 2019 Mar 18.


Introduction: Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs).

Methods: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model.

Results: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model.

Conclusion: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

Keywords: 2′-Benzoyloxycinnamaldehyde; 2′-Hydroxycinnamaldehyde; Glioblastoma tumorsphere; Invasiveness; Mesenchymal transition; Temozolomide.

MeSH terms

  • Acrolein / analogs & derivatives
  • Acrolein / pharmacology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzoates / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cinnamates / pharmacology*
  • Drug Therapy, Combination
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Glioblastoma / physiopathology
  • Humans
  • Mice, Nude
  • Neoplasm Invasiveness* / pathology
  • Neoplasm Invasiveness* / physiopathology
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / pathology
  • Neoplastic Stem Cells / physiology
  • Temozolomide / pharmacology*
  • Tissue Scaffolds


  • 2'-benzoyloxycinnamaldehyde
  • Antineoplastic Agents
  • Benzoates
  • Cinnamates
  • p-hydroxycinnamaldehyde
  • Acrolein
  • Adenosine Triphosphate
  • Temozolomide