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J Thorac Cardiovasc Surg 2006;132:1356-1362
© 2006 The American Association for Thoracic Surgery

General Thoracic Surgery

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

Wen-Shuz Yeow, PhD, Aris Baras*, Alex Chua*, Duc M. Nguyen*, Shailen S. Sehgal, BS{dagger}, David S. Schrump, MD, FACS, Dao M. Nguyen, MD, MS, FRCSC, FACS*

Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication May 5, 2006; revisions received May 19, 2006; accepted for publication July 12, 2006.

* Address for reprints: Dao M. Nguyen, MD, Room 4W-4-3940, 10 Center Dr, Bethesda, MD 20892. (Email: dao_nguyen{at}nih.gov).

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 µmol/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.

Abbreviations and Acronyms IC50 = inhibitory concentration of 50%; MTT = (4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide; TNF = tumor necrosis factor; TRAIL = tumor necrosis factor–related apoptosis-inducing ligand; TUNEL = terminal deoxynucleotidyltransferase–mediated dUTP nick-end labeling


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Discussion
J. Thorac. Cardiovasc. Surg. 2006 132: 1362. [Extract] [Full Text] [PDF]



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