Role of elevated pressure in TRAIL-induced apoptosis in human lung carcinoma cells

Apoptosis. 2010 Dec;15(12):1517-28. doi: 10.1007/s10495-010-0525-5.


TNF-related apoptosis-inducing ligand (TRAIL, Apo2L) is a promising anticancer agent with high specificity for cancer cells. Many strategies have been proposed to enhance the sensitivity of cancer cells to TRAIL-mediated apoptosis, including the use of combination treatment with conventional cancer therapies. However, few reports have evaluated the effects of TRAIL in combination with mechanical stress, which can also cause apoptosis of cancer cells. In the present study, we describe a custom-designed culture system that delivers two atmospheres of elevated pressure (EP) by using compressed air, and which enhances the sensitivity of cancer cells to TRAIL-mediated apoptosis. The combination of TRAIL and EP significantly increased apoptosis of human H460 lung cancer cells more than hyperbaric normoxia or normobaric mild hyperoxia. EP-potentiating TRAIL-mediated apoptosis of H460 cells was accompanied by up-regulated death receptor 5 (DR5), activation of caspases, decreased mitochondrial membrane potential, and reactive oxygen species production. We also observed EP-induced sensitization of TRAIL-mediated apoptosis in other cancer cell types. In contrast, human normal cells showed no DNA damage or cell death when exposed to the combined treatment. In a chicken chorioallantoic membrane model, EP enhanced TRAIL-mediated apoptosis of tumors that developed from transplanted H460 cells. Collectively, EP enhanced TRAIL-induced apoptosis of human lung carcinoma cells in vitro and in vivo. These findings suggest that EP is a mechanical and physiological stimulus that might have utility as a sensitizing tool for cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis* / drug effects
  • Apoptosis* / physiology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Chick Embryo
  • Combined Modality Therapy
  • Female
  • Fetus
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Membrane Potential, Mitochondrial / drug effects*
  • Membrane Potential, Mitochondrial / physiology
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Recombinant Proteins* / genetics
  • Recombinant Proteins* / pharmacology
  • Recombinant Proteins* / therapeutic use
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stress, Mechanical
  • TNF-Related Apoptosis-Inducing Ligand* / genetics
  • TNF-Related Apoptosis-Inducing Ligand* / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand* / therapeutic use


  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • Reactive Oxygen Species
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Recombinant Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Caspases