The role of the 3D environment in hypoxia-induced drug and apoptosis resistance

Jun W. Kim, Won Jin Ho, Benjamin M. Wu

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Background: 3D tumors express different adhesion receptors from those expressed in monolayers, leading to a distinct microenvironment. The third dimension also brings mass transport into relevance, as inadequate diffusion of oxygen produces hypoxia. This study investigates the effects of distinct 3D environments on hypoxia-associated apoptosis and drug resistance. Materials and Methods: Under hypoxia and normoxia, U251 glioma cells and U87 astrocytoma cells were grown as spheroids on flat substrates, scaffolds seeded with dispersed cells, and spheroid-seeded scaffolds. The samples were subsequently treated with doxorubicin and resveratrol, known inducers of apoptosis. Results: All 3D environments induced increased but distinct resistance to apoptosis, as evident by lower caspase-3 activity, and higher production of anti-apoptotic proteins BCL-2 and survivin. Hypoxic monolayers also exhibited higher resistance to doxorubicin and higher production of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), but lower production of BCL-2 and survivin. Conclusion: These findings suggest that in vitro, 3D models acquire greater apoptosis resistance via up-regulation of anti-apoptotic proteins, and that the precise mechanism depends on the individual 3D microenvironment.

Original languageEnglish (US)
Pages (from-to)3237-3245
Number of pages9
JournalAnticancer research
Issue number10
StatePublished - Oct 2011
Externally publishedYes


  • Anticancer drug and apoptosis
  • Anticancer drug resistance
  • Cell-to-cell interaction/adhesion molecules
  • Characteristics of cancer cells
  • Chemotherapy
  • Drug sensitivity/drug resistance-relating factors/gene expression analysis
  • Evaluation and prediction of pharmacological effects
  • Screening systems

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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