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.
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Authors | Dongkyoo Park, Andrew T Magis, Rui Li, Taofeek K Owonikoko, Gabriel L Sica, Shi-Yong Sun, Suresh S Ramalingam, Fadlo R Khuri, Walter J Curran, Xingming Deng |
Journal | Cancer research
(Cancer Res)
Vol. 73
Issue 17
Pg. 5485-96
(Sep 01 2013)
ISSN: 1538-7445 [Electronic] United States |
PMID | 23824742
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABT-737
- Acridines
- Aminopyridines
- BAK1 protein, human
- BXI-61
- BXI-72
- Benzimidazoles
- Biphenyl Compounds
- Nitrophenols
- Piperazines
- Proto-Oncogene Proteins c-bcl-2
- Small Molecule Libraries
- Sulfonamides
- bcl-2 Homologous Antagonist-Killer Protein
- bcl-X Protein
- Cytochromes c
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Topics |
- Acridines
(pharmacology)
- Aminopyridines
(pharmacology)
- Animals
- Apoptosis
(drug effects, radiation effects)
- Benzimidazoles
(pharmacology)
- Biphenyl Compounds
(pharmacology)
- Blotting, Western
- Cell Proliferation
(drug effects, radiation effects)
- Cytochromes c
(metabolism)
- Female
- Humans
- Lung
(cytology, drug effects)
- Lung Neoplasms
(drug therapy, mortality, pathology)
- Mice
- Mice, Nude
- Nitrophenols
(pharmacology)
- Piperazines
(pharmacology)
- Protein Multimerization
- Proto-Oncogene Proteins c-bcl-2
(antagonists & inhibitors, metabolism)
- Radiation Tolerance
(drug effects)
- Radiation, Ionizing
- Small Molecule Libraries
- Sulfonamides
(pharmacology)
- Survival Rate
- bcl-2 Homologous Antagonist-Killer Protein
(antagonists & inhibitors, metabolism)
- bcl-X Protein
(antagonists & inhibitors, metabolism)
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