AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

Donzella, G A; Schols, Dominique; Lin, Steven; Esté, José A.; Nagashima, Kiichi; Maddon, Paul J.; Allaway, Graham P.; Sakmar, Thomas P.; Henson, Geoffrey; Clercq, Erik De; Moore, John P.

doi:10.1038/nm0198-072

Cited by 728 publications

(482 citation statements)

References 47 publications

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“…One such compound is a bicyclam derivative AMD3100 (AnorMED, Langley, BC, Canada). 30 In a phase I clinical trial, AMD3100 was well tolerated without any significant toxicity. 31 This suggests that AMD3100 or similar compounds may potentially be used to interfere with tumor progression and metastasis in bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Retz

Sidhu

Blaveri

et al. 2004

Intl Journal of Cancer

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Transitional cell carcinoma of the urinary bladder remains life threatening due to the high occurrence of metastases. Emerging evidence suggests that chemokines and their receptors play a critical role in tumor metastases. In our study, we performed a systematic analysis of the mRNA and protein expression levels of all 18 chemokine receptors in normal urothelium and bladder cancer. CXCR4 was the only chemokine receptor whose mRNA expression level was upregulated in bladder cancer cell lines as well as in invasive and locally advanced bladder cancer tissue samples (pT2-pT4). In contrast, superficial bladder tumors (pTa and pT1) displayed low CXCR4 expression levels and normal urothelial cells were negative for CXCR4. Immunohistochemistry of a bladder cancer tissue microarray (TMA) confirmed that a subgroup of invasive bladder cancers revealed a high CXCR4 protein expression, while superficial bladder tumors showed low immunoreactivity. To investigate the functional significance of CXCR4 expression, we performed migration and invasion assays. Exposure of CXCR4-positive bladder cancer cells to CXCL12 in a Boyden chamber type assay provoked a significant increase in migration as well as invasion across a Matrigel barrier. Enhanced migration and invasion were inhibited by a CXCR4-specific blocking antibody. In contrast, normal urothelial cells did not respond to CXCL12 and lacked chemotactic migration. In conclusion, bladder cancer cells express CXCR4 progressively with advanced tumorigenesis and this receptor interacts with CXCL12 to mediate tumor chemotaxis and invasion through connective tissue. These properties identify CXCR4 as a potential target for the attenuation of bladder cancer metastases. © 2004 Wiley-Liss, Inc.Key words: chemokine; bladder cancer; metastasis; migration; invasion Transitional cell carcinoma of the bladder is the most frequent tumor of the urinary tract. Despite advances in early detection and therapy, bladder cancer remains life threatening due to the high occurrence of metastases. Radical cystectomy is the preferred treatment for muscle-invasive bladder cancer in the United States, Japan and some countries of Europe. However, at least 50% of patients with locally advanced disease are expected to develop systemic progression within 3 years. 1 Patients suffering from metastatic bladder cancer are commonly treated with systemic chemotherapy. Analyzing survival rates from standard chemotherapy schedules such as M-VAC (methotrexate, vinblastine, adriamycin and cisplatin), results are more or less discouraging. In the Loehrer trial, only 5 of 133 (3.7%) of the patients randomized to M-VAC were alive at the 6-year follow-up time. These results indicate that patients with systemic metastases continue to be incurable by chemotherapy. 2,3 Despite the fact that it is the metastases rather than the primary tumors that cause most cancer deaths, there has been little progress in identifying drugs to specifically block metastases.Metastasis is not a simple phenomenon, but a highly organized process com...

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Section: Discussionmentioning

confidence: 99%

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Retz

Sidhu

Blaveri

et al. 2004

Intl Journal of Cancer

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“…37 Moreover, there have been several reports of using small molecules or chemokines to block HIV-1 infection and to decrease viral load in HIV-infected individuals. [38][39][40][41] Hence, targeting HIV-1 co-receptors to block virus entry is a reasonable approach to the control of HIV-1 infection, thus warranting further evaluation in animal model and human trials.…”

Section: Discussionmentioning

confidence: 99%

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

Schroers

et al. 2002

Gene Ther

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Intrakines, modified intracellular chemokines, offer a novel strategy to prevent cellular entry of HIV-1 by blocking the surface expression of HIV-1 co-receptors. To investigate potential clinical applications of the RANTES-intrakine, we explored the use of HIV-1-based lentiviral vectors for therapeutic gene transfer into T-lymphocytes. RANTES-intrakine genes can be efficiently transduced into primary human Tlymphocytes by lentiviral vectors, especially when human Tlymphocytes were stimulated with CD3 and CD28 antibodies. The transduced T cells showed decreased surface expression of the chemokine receptor CCR-5, as well as CCR-1 and CCR-3. This lentivirus-mediated approach to

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“…Pre-incubation with the bicyclam AMD3100, a highly selective CXCR4 antagonist [17,18] completely abolished the negative effect of CXCL12 on CM shortening and Ca 2+ transients (Figs. 4A and B).…”

Section: Cxcl12 Effects On CM Contractility Are Mediated Through Cxcr4mentioning

confidence: 92%

CXCR4 modulates contractility in adult cardiac myocytes

Pyo¹,

Sui²,

Dhume³

et al. 2006

Journal of Molecular and Cellular Cardiology

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The inflammatory response is critical to the development and progression of heart failure. Chemokines and their receptors are a distinct class of inflammatory modulators that may play a role in mediating myocardial dysfunction in heart failure. Levels of the chemokine CXCL12, also known as stromal cell-derived factor (SDF), and its receptor, CXCR4, are elevated in patients with heart failure, and we undertook this study to determine whether this chemokine system can directly affect cardiac function in the absence of leukocytes. Murine papillary muscles and adult rat cardiac myocytes treated with CXCL12, the only identified ligand of CXCR4, demonstrate blunted inotropic responses to physiologic concentrations of calcium. The negative inotropic effects on cardiac myocytes are accompanied by a proportional diminution of calcium transients. The effects are abrogated by AMD3100, a specific CXCR4 inhibitor. Overexpression of the receptor through adenoviral infection with a CXCR4 construct accentuates the negative inotropic effects of CXCL12 on cardiac myocytes during calcium stimulation. CXCR4 activation also attenuates beta-adrenergicmediated increases in calcium mobilization and fractional shortening in cardiac myocytes. In electrophysiologic studies, CXCL12 decreases forskolin-and isoproterenol-induced voltage-gated L-type calcium channel activation. These studies demonstrate that activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function. The specific mechanism of action involves alterations of calcium channel activity on the membrane. The presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction.

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AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

Cited by 728 publications

References 47 publications

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

CXCR4 modulates contractility in adult cardiac myocytes

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