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

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

doi:10.18632/oncotarget.24580

Cited by 7 publications

(10 citation statements)

References 42 publications

(58 reference statements)

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“…Remarkably, this compound has the capability to prevent VEGF-mediated tumor angiogenesis induced by the CXCR4/CXCL12 axis in breast tumor xenografts [124] and exerts anti-metastatic activity in breast cancer in cultured cells and animal models [125,126,127]. The other anti-HIV SDF-1 competitor, Nef-M1, an apoptotic peptide that encompasses the residues 50 to 60 of the HIV-1 Nef protein (sequence: Thr–Asn–Ala–Ala–Cys–Ala–Trp–Leu–Glu–Ala–Gln), not only inhibits the growth of primary breast tumors and related metastasis [128,129], but also prevents breast tumor angiogenesis and epithelial-to-mesenchymal transition [130]. The CXCR4 antagonist GST–NT21MP, a 21-mer synthetic peptide derived from the N-terminal extremity of the viral macrophage inflammatory protein II, also called vMIP-II (NT21MP sequence: Leu–Gly–Ala–Ser–Trp–His–Arg–Pro–Asp–Lys–Cys–Cys–Leu–Gly–tyr–Gln–Lys–Arg–Pro–Leu–Pro, residues 1–21), abrogates SDF-1-induced cell growth, breast cancer cells adhesion and migration, and delays pulmonary metastasis in vivo [131,132].…”

Section: Gpcrs In Breast Cancer: Signaling Biology and Modulatorsmentioning

confidence: 99%

GPCR Modulation in Breast Cancer

Lappano

Jacquot

Maggiolini

2018

IJMS

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Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors involved in the development and progression of many tumors including breast cancer. Here we discuss data regarding GPCR-mediated signaling, pharmacological properties and biological outputs toward breast cancer tumorigenesis and metastasis. Furthermore, we address several drugs that have shown an unexpected opportunity to interfere with GPCR-based breast tumorigenic signals.

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Section: Gpcrs In Breast Cancer: Signaling Biology and Modulatorsmentioning

confidence: 99%

GPCR Modulation in Breast Cancer

Lappano

Jacquot

Maggiolini

2018

IJMS

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“…In order to verify the effectiveness of this method, the simulation experiment is designed. The above analysis method is compared with the previous hypersensitivity method (Fülle et al 2018), selective targeting apoptosis method (Huang et al, 2018). The time-consuming, accuracy, and stability of the solution are compared.…”

Section: Simulation Experiments Analysismentioning

confidence: 99%

“…A reasonable prediction and evaluation of the actual experimental problems by these properties. Therefore, the study of PDE model has great practical value and objective significance (Fülle et al, 2018; Huang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Asymptotic and stability analysis of solutions for a Keller Segel chemotaxis model

Zhang

2021

Concurrent Engineering

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A kind of Keller Segel chemotaxis model has a wide range of applications, but its coupling relationship is very complex. The commonly used method of constructing the upper and lower solutions is no longer suitable for the model solution, which results in a long time for its analysis. In this paper, we propose a method to analyze the asymptotic behavior and stability of a Keller Segel chemotaxis model. The previous methods of first formally and then rigorously, the asymptotic expansion of these monotone steady states, and then we use this fine information on the spike to prove its local asymptotic stability. Moreover, we obtain the uniqueness of such steady states. The asymptotic behavior of the solution of a Keller Segel chemotaxis model is analyzed, and the asymptotic rate is calculated; According to the limitation of Neumann boundary condition, the complete blow up of chemotaxis model solution and the stability of the initial value of the complete blow up time are studied, and the asymptotic and stability analysis of a kind of Keller Segel chemotaxis model solution is completed. The experimental results show that the proposed method takes less time to solve a kind of Keller Segel chemotaxis model, improves the efficiency of the solution, and the accuracy of the solution is higher.

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“…38–41 In recent years, some promising anti-HIV-1 entry small-molecule inhibitors that target CXCR4 have been reported (Table 1). 38,41–48…”

Section: Cxcr4-targeted Small-molecule Hiv-1 Entry Inhibitorsmentioning

confidence: 99%

“…These two compounds show selectivity toward blocking HIV-1 entry over CXCR4 antagonism, based on studies of HIV-1 IIIB MAGI entry and of CXCL12-induced calcium flux. 45 Compounds 5–7, which share N-aryl piperazines, are another series of CXCR4-antagonists. Compounds 6 and 7 exhibit high anti-HIV-1 entry activity at very low nanomolar levels (20 and 0.5 nM, respectively).…”

Section: Cxcr4-targeted Small-molecule Hiv-1 Entry Inhibitorsmentioning

confidence: 99%

Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors

Zhang

Zhu

Cao

et al. 2020

Exp Biol Med (Maywood)

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The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and its expression correlates with more profound pathogenicity, rapid progression to acquired immunodeficiency syndrome (AIDS), and greater AIDS-related mortality. There is still no cure for AIDS and no method for preventing or eradicating HIV-1 infection. HIV-1 entry begins with the interaction of the viral envelope glycoprotein gp120 and the primary receptor CD4, and subsequently with the coreceptors, CCR5 or CXCR4, on the host cells. Blocking the interaction of HIV-1 and its coreceptors is therefore a promising strategy for developing new HIV-1 entry inhibitors. This approach has a dual benefit, as it prevents HIV-1 infection and progression while also targeting the reservoirs of HIV-1 infected, coreceptor positive macrophages and memory T cells. To date, multiple classes of CXCR4-targeted anti-HIV-1 inhibitors have been discovered and are now at different preclinical and clinical stages. In this review, we highlight the studies of CXCR4-targeted small-molecule and peptide HIV-1 entry inhibitors discovered during the last two decades and provide a reference for further potential HIV-1 exploration in the future. Impact statement This minireview summarized the current progress in the identification of CXCR4-targeted HIV-1-entry inhibitors based on discovery/developmental approaches. It also provided a discussion of the inhibitor structural features, antiviral activities, and pharmacological properties. Unlike other reviews on anti-HIV-1 drug development, which have generally emphasized inhibitors that target intracellular viral replication and host genomic integration, this review focused on the drug discovery approaches taken to develop viral-entry inhibitors aimed at disturbing the initial step of viral interaction with uninfected host cells and preventing the subsequent viral replication/genomic integration. This review amalgamated recently published and important work on bivalent CXCR4-targeted anti-HIV-1-entry candidates/conjugates, discussed the research challenges faced in developing drugs to prevent and eradicate HIV-1 infection, and provided a perspective on strategies that can lead to future drug discoveries. The findings and strategies summarized in this review will be of interest to investigators throughout the microbiological, pharmaceutical, and translational research communities.

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

Cited by 7 publications

References 42 publications

GPCR Modulation in Breast Cancer

GPCR Modulation in Breast Cancer

Asymptotic and stability analysis of solutions for a Keller Segel chemotaxis model

Discoveries and developments of CXCR4-targeted HIV-1 entry inhibitors

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