Oncotarget

Research Papers:

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

Ming-Bo Huang, Kyle E. Giesler, Brooke M. Katzman, Anthony R. Prosser, Valarie Truax, Dennis C. Liotta, Lawrence J. Wilson and Vincent C. Bond _

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Oncotarget. 2018; 9:16996-17013. https://doi.org/10.18632/oncotarget.24580

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Abstract

Ming-Bo Huang1,*, Kyle E. Giesler2,*, Brooke M. Katzman2, Anthony R. Prosser2, Valarie Truax2, Dennis C. Liotta2, Lawrence J. Wilson2 and Vincent C. Bond1

1Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia 30310, United States

2Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States

*These authors contributed equally to this work

Correspondence to:

Vincent C. Bond, email: vbond@msm.edu

Keywords: CXCR4 compounds; breast cancer cell lines; selective targeting apoptosis; depolarization; NefM1

Received: October 07, 2017     Accepted: February 20, 2018     Epub: February 26, 2018     Published: March 30, 2018

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.


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