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

Uchida, Daisuke; Kuribayashi, Nobuyuki; Kinouchi, Makoto; Sawatani, Yutaï¿1⁄2; Shimura, Michikoï¿1⁄2; Mori, Toshimitsu; Hasegawa, Tomonoriï¿1⁄2; Miyamoto, Youji; Kawamata, Hitoshi

doi:10.3892/or.2018.6400

Cited by 13 publications

(8 citation statements)

References 31 publications

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“…In stark contrast, AMD3100 and niacin alone had no cytotoxic effects on the lymphoma cell lines. These findings are in line with already published data, where only the inhibition of migration of malignant and non-malignant cells for AMD3100 and growth inhibition for AMD070 have been reported [54,55]. However, our data indicate that the cytotoxic and/or apoptotic effects of AMD070 are increased by the addition of niacin and that these effects depend on the CXCR4 and CXCR7 expression patterns.…”

Section: Discussionsupporting

confidence: 93%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

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In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

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Section: Discussionsupporting

confidence: 93%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…In stark contrast, AMD3100 and niacin alone had no cytotoxic effects on lymphoma cell lines. These findings are in line with already published data, in which just inhibition of migration of malignant and non-malignant cells for AMD3100 and additionally growth inhibition for AMD070 were reported [42,43]. However, our data indicate that the cytotoxic and/ or apoptotic effects of AMD070 are increased by the addition of niacin and that these effects depend on the CXCR4 and CXCR7 expression patterns.…”

Section: Discussionsupporting

confidence: 93%

The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

Pansy

Feichtinger

Ehall

et al. 2019

Preprint

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In tumour cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls. Interestingly, high expression of CXCR4 was associated with poor clinical outcome. Furthermore, in corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Furthermore, the niacin derivate of the CXCR4 antagonist AMD070, which was synthesized by us, demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of certain pro-apoptotic genes in CXCR4 positive lymphoma cell lines. Finally, WK1 treatment resulted in reduced expression of JNK-, ERK1/2- and NFκB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

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“…In preclinical studies, overexpression of CXCR4 has been demonstrated to dramatically increase lung and liver metastases of murine pancreatic cancer in tail vein metastasis assays in nude mice (106). Consistently, antagonizing CXCR4 inhibited lung metastasis of human tongue squamous cell carcinoma (107), esophageal cancer (108), breast cancer (109) in immunocompromized mice. Intra-arterially injected circulating CXCR4-expressing melanoma cells require SDF-1 signaling by mesenchymal stem cells that act as pericytes for extravasation to bone and liver and perivascular niche formation as demonstrated by humanized heterotopic bone formation assay (110).…”

Section: Sdf-1/cxcr4 Function In Tumor Biologymentioning

confidence: 80%

Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer

Schilbach²,

et al. 2018

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Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects—tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy—several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches.

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

Cited by 13 publications

References 31 publications

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer

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