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

AbstractBACKGROUND:
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.
AuthorsJun W Kim, Won Jin Ho, Benjamin M Wu
JournalAnticancer research (Anticancer Res) Vol. 31 Issue 10 Pg. 3237-45 (Oct 2011) ISSN: 1791-7530 [Electronic] Greece
PMID21965731 (Publication Type: Journal Article)
Chemical References
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Survivin
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Doxorubicin
Topics
  • Apoptosis (drug effects)
  • Cell Hypoxia (drug effects)
  • Cell Line, Tumor
  • Down-Regulation (drug effects)
  • Doxorubicin (pharmacology)
  • Drug Resistance, Neoplasm (drug effects)
  • Fibroblast Growth Factor 2 (metabolism)
  • Humans
  • Image Processing, Computer-Assisted
  • Inhibitor of Apoptosis Proteins (metabolism)
  • Inhibitory Concentration 50
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Spheroids, Cellular (pathology)
  • Survivin
  • Tissue Scaffolds (chemistry)
  • Tumor Microenvironment (drug effects)
  • Up-Regulation (drug effects)
  • Vascular Endothelial Growth Factor A (metabolism)

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