Abstract
Bcl-XL is a major antiapoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1, or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak, and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. On the basis of our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acridines / pharmacology*
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Aminopyridines / pharmacology*
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Benzimidazoles / pharmacology*
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Biphenyl Compounds / pharmacology*
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Blotting, Western
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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Cytochromes c / metabolism
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Female
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Humans
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Lung / cytology
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Lung / drug effects*
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Nitrophenols / pharmacology*
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Piperazines / pharmacology
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Protein Multimerization
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Radiation Tolerance / drug effects*
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Radiation, Ionizing
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Small Molecule Libraries*
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Sulfonamides / pharmacology*
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Survival Rate
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bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-X Protein / antagonists & inhibitors*
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bcl-X Protein / metabolism
Substances
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ABT-737
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Acridines
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Aminopyridines
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BAK1 protein, human
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BXI-61
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BXI-72
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Benzimidazoles
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Biphenyl Compounds
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Small Molecule Libraries
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Sulfonamides
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-X Protein
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Cytochromes c