Novel Small-Molecule Inhibitors of Bcl-XL to Treat Lung Cancer

• Type of Material: Article
• Authors: Dongkyoo Park, Emory University; Andrew T. Magis, University of Illinois; Rui Li, Emory University; Taofeek Owonikoko, Emory University; Gabriel Sica, Emory University; Shi-Yong Sun, Emory University; Suresh Ramalingam, Emory University; Fadlo Khuri, Emory University; Walter Curran Jr, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2013-09-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2013 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-12-2272
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 73
• Issue: 17
• Start Page: 5485
• End Page: 5496
• Grant/Funding Information: This work was supported by NCI, National Institutes of Health grants R01CA112183, R01CA136534, Flight Attendant Medical Research Institute Clinical Innovator Awards, and by NASA grant NNX12AC30G.
• Keywords: BH3 MIMETIC ABT-737; BAK; RESISTANCE; Life Sciences & Biomedicine; Science & Technology; MCL-1; IONIZING-RADIATION; INDUCED APOPTOSIS; BCL-X(L); FAMILY INHIBITOR; CELL-LINES; Oncology; GENE-EXPRESSION
• Research Categories: Health Sciences, Oncology

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.