Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

Hout, Anneleen Van; D’huys, Thomas; Oeyen, Merel; Schols, Dominique; Loy, Tom Van

doi:10.1371/journal.pone.0176057

Cited by 36 publications

(33 citation statements)

References 40 publications

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“…In clinical trials, Stone et al demonstrated that no apparent acute toxicity was present in oral bioavailability studies using AMD070 (20), suggesting that CXCR4 is a safe therapeutic target. In addition, more recent investigations have identified several candidate inhibitors of CXCR4 in CXCL12 competition binding studies (36). Although AMD3100 is the only currently clinically available inhibitor, these new compounds, including AMD070, may have the potential to become novel candidates for CXCR4-targeting therapies.…”

Section: Discussionmentioning

confidence: 99%

Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells

et al. 2018

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We have previously demonstrated that the stromal cell‑derived factor (SDF‑1)/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been revealed that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4‑related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF‑1/CXCR4 axis in B88‑SDF‑1 oral cancer cells, which express high levels of SDF‑1 and CXCR4. Although treatment with AMD070 did not affect the anchorage‑dependent growth of B88‑SDF‑1 cells, it significantly suppressed the anchorage‑independent growth. Moreover, the SDF‑1/CXCR4‑dependent migration and invasion of B88‑SDF‑1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88‑SDF‑1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88‑SDF‑1 cells in nude mice. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells

et al. 2018

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“…CXCL12-induced calcium fluxes were measured using the FLIPR Tetra (Molecular Devices, Sunnyvale, USA) as described previously [ 19 ] with only minor adaptations. HT-29 cells were seeded at 6x10 4 cells per well instead of 2x10 4 cells per well for U87.CD4.CXCR4 cells.…”

Section: Methodsmentioning

confidence: 99%

“…Compounds that had to pre-incubate overnight (PTX, YM-254890) were added manually to the cells the day prior to the experiment. After washing the cells as previously described [ 19 ], the cells were exposed to the compound for one hour. After compound pre-incubation, cells were stimulated with CXCL12.…”

Section: Methodsmentioning

confidence: 99%

“…CXCR4 and CXCR7 are promising candidates for pharmacological targeting, which necessitates the development of drug discovery assays. In the case of CXCR4, G-protein-dependent calcium mobilization assays and receptor binding studies are often used as screening tools to identify receptor antagonists [ 19 , 20 ], whereas in the case of CXCR7, β-arrestin recruitment assays are the primary choice given its atypical signaling properties. Here, we evaluate in detail the use of cellular electric impedance analysis, a label-free and non-invasive method [ 21 , 22 ], as an alternative way to analyze CXCR4 and CXCR7 signaling.…”

Section: Introductionmentioning

confidence: 99%

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Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements

et al. 2017

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The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect agents that modulate receptor activity, are of key importance for drug discovery. We evaluated the potential of cellular electric impedance for this purpose. Dose-dependent and specific stimulation of CXCR4 was detected upon addition of its unique chemokine ligand CXCL12. The response magnitude correlated with the CXCR4 expression level. Gαi coupling and signaling contributed extensively to the impedance response, whereas Gαq- and Gβγ-related events had only minor effects on the impedance profile. CXCR7 signaling could not be detected using impedance measurements. However, increasing levels of CXCR7 expression significantly reduced the CXCR4-mediated impedance readout, suggesting a regulatory role for CXCR7 on CXCR4-mediated signaling. Taken together, cellular electric impedance spectroscopy can represent a valuable alternative pharmacological cell-based assay for the identification of molecules targeting CXCR4, but not for CXCR7 in the absence of CXCR4.

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“…Consequently, inhibition of this axis is suggested as an attractive target for therapeutic intervention. There are several CXCR4 inhibitors, such as AMD3100 (plerixafor, nonpeptidic CXCR4 antagonist), AMD3465 (non-peptidic CXCR4 antagonist) and CTCE-9908 (CXCL12 peptidic analogue) [119]. Although these molecules act by direct inhibition of CXCR4 ( Figure 1) and show efficacy when compared to other chemotherapeutic agents, their toxic effects are not well understood yet [98].…”

Section: Sonic Hedgehog (Shh) Pathway and Cxcl12/cxcr4 Axis In Mbmentioning

confidence: 99%

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma

et al. 2018

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Medulloblastoma (MB) is the most common malignant brain tumor occurring in children, and although high long-term survival rates have been reached with current therapeutic protocols, several neurological injuries are still observed among survivors. It has been shown that the development of MB is highly dependent on the microenvironment surrounding it and that the CXCL12 chemokine and its receptor, CXCR4 and the Sonic Hedgehog (SHH) pathway are crucial for cerebellar development, coordinating proliferation and migration of embryonic cells and malfunctions in these axes can lead to MB development. Indeed, the concomitant overactivation of these axes was suggested to define a new MB molecular subgroup. New molecules are being studied, aiming to inhibit either CXCR4 or the SHH pathways and have been tested in preclinical settings for the treatment of cancers. The use of these molecules could improve MB treatment and save patients from aggressive surgery, chemotherapy and radiotherapy regimens, which are responsible for severe neurological consequences. This review aims to summarize current data about the experimental inhibition of CXCR4 and SHH pathways in MB and its potential implications in treatment of this cancer.

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Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors

Cited by 36 publications

References 40 publications

Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells

Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells

Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements

Potential use of CXCL12/CXCR4 and sonic hedgehog pathways as therapeutic targets in medulloblastoma

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