Gossypol, a phytochemical with BH3-mimetic property, sensitizes cultured thoracic cancer cells to Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand.

Abstract

OBJECTIVES:

Chemotherapeutic agents sensitize cancer cells to Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) via recruitment of the mitochondria-dependent activation of caspase and induction of apoptosis. This study was designed to evaluate whether gossypol, a phytochemical compound with BH3-mimetic property that functions as an inhibitor of Bcl2/BclXL, would sensitize cultured thoracic cancer cells to this death-inducing ligand.

METHODS:

Cancer cell lines from the lung (H460, H322), the esophagus (TE2, TE12), and the pleura (H290, H211) or primary normal cells were treated with gossypol+Apo2L/TRAIL combinations. Cell viability and apoptosis were evaluated by (4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) assays, respectively. Caspase 9 and 3 specific proteolytic activity in combination-treated cells was determined by fluorometric enzymatic assay.

RESULTS:

Gossypol, selectively cytotoxic to cancer cells and not primary normal cells, significantly sensitized thoracic cancer cells to Apo2L/TRAIL as indicated by 1.5- to more than 10-fold reduction of Apo2L/TRAIL 50% inhibitory concentration values in cells treated with gossypol+Apo2L/TRAIL combinations. Whereas less than 20% of cancer cells exposed to either gossypol (5 micromol/L) or Apo2L/TRAIL (20 ng/mL) were dead, more than 90% of cells treated with the drug combinations were apoptotic. Combination-induced cytotoxicity and apoptosis was completely abrogated either by overexpression of Bcl2 or by the selective caspase 9 inhibitor. This combination was not toxic to normal cells.

CONCLUSION:

Gossypol profoundly sensitizes thoracic cancer cells to the cytotoxic effect of Apo2L/TRAIL via activation of the mitochondria-dependent death signaling pathway. This study provides evidence for the profound anticancer activity of this drug combination and should be further evaluated as a novel targeted molecular therapeutic for thoracic cancers.

• Authors: Wen-Shuz Yeow, Aris Baras, Alex Chua, Duc M Nguyen, Shailen S Sehgal, David S Schrump, Dao M Nguyen
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 132 Issue 6 Pg. 1356-62 (Dec 2006) ISSN: 1097-685X [Electronic] United States
• PMID: 17140955 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• TNF-Related Apoptosis-Inducing Ligand
• Gossypol

Topics

• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Death (drug effects)
• Esophageal Neoplasms (pathology)
• Gossypol (pharmacology)
• Humans
• Lung Neoplasms (pathology)
• Mesothelioma (pathology)
• Pleural Neoplasms (pathology)
• TNF-Related Apoptosis-Inducing Ligand (drug effects, physiology)
• Tumor Cells, Cultured