Small molecule CXCR4 antagonists block the HIV-1 Nef/CXCR4 axis and selectively initiate the apoptotic program in breast cancer cells

• Type of Material: Article
• Authors: Ming-Bo Huang, Morehouse School of Medicine; Kyle E. Giesler, Emory University; Brooke M. Katzman, Emory University; Anthony R. Prosser, Emory University; Valarie Truax, Emory University; Dennis C Liotta, Emory University; Lawrence J. Wilson, Emory University; Vincent C. Bond, Morehouse School of Medicine
• Language: English
• Date: 2018-03-30
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Huang et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.24580
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 9
• Issue: 24
• Start Page: 16996
• End Page: 17013
• Grant/Funding Information: This research and the facilities used for the research were supported by the following grants: NIH/NIMHD 8G12MD007602; NIH/NIMHD 8U54MD007588; NIH/NIMHD S21MD000101; NIH/NCRR C06 RR18386; NIH/NCRR G20 RR031196.
• Keywords: CXCR4 compounds; breast cancer cell lines; selective targeting apoptosis; NefM1; depolarization
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

Abstract

The chemokine receptor CXCR4 plays an integral role in the development of highly metastatic breast cancer and in the pathogenesis of chronic HIV infection. In this study, we compared the effects of CXCR4 antagonists on apoptosis induction in hematopoietic cells and in tumor cells. We incubated cells expressing CXCR4 with a series of CXCR4 antagonists and subsequently exposed the cultures to a pro-apoptotic peptide derived from the HIV-1 Nef protein (NefM1). The NefM1 peptide contains residues 50–60 of Nef and was previously shown to be the sequence necessary for Nef to initiate the apoptotic program through CXCR4 signaling. We found that several of the compounds studied potently blocked Nef-induced apoptosis in Jurkat T-lymphocyte cells. Interestingly, many of the same compounds selectively triggered apoptosis in MDA-MB-231 breast cancer cells, in some cases at sub-nanomolar concentrations. None of the compounds were toxic to lymphocyte, monocyte or macrophage cells, suggesting that aggressive breast cancer carcinomas may be selectively targeted and eliminated using CXCR4-based therapies without additional cytotoxic agents. Our results also demonstrate that not all CXCR4 antagonists are alike and that the observed anti-Nef and pro-apoptotic effects are chemically tunable. Collectively, these findings suggest our CXCR4 antagonists have promising clinical utility for HIV or breast cancer therapies as well as being useful probes to examine the link between CXCR4 and apoptosis.