CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth

Beider, Katia; Begin, Michal; Abraham, Michal; Wald, Hanna; Weiss, Ido D.; Wald, Ori; Pikarsky, Eli; Zeira, Evelyne; Eizenberg, Orly; Galun, Eithan; Hardan, Izhar; Engelhard, Dan; Nagler, Arnon; Peled, Amnon

doi:10.1016/j.exphem.2010.11.010

Cited by 84 publications

(72 citation statements)

References 45 publications

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“…In addition, BKT140 was shown to mediate a potent cytotoxic activity against various hematologic malignancies, including multiple myeloma (MM), acute promyelocytic leukemia (APL), and non-Hodgkin lymphoma (NHL) cells, respectively (24,26). In the current work, we were able to show that BKT140 treatment induced a modest inhibition of CML cell growth in vitro.…”

Section: Discussionsupporting

confidence: 57%

“…Previously, we have shown that the high affinity CXCR4 antagonist BKT140 demonstrates an effective antitumor effect both in vitro and in vivo in various hematologic malignancies and enhances the proapoptotic effect of antileukemic compounds (24). In the current study, we evaluated the effect of BKT140 on CML cell viability and sensitivity to imatinib in the presence of BMCSs.…”

Section: Introductionmentioning

confidence: 99%

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Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

Beider

Darash-Yahana

Blaier

et al. 2014

Molecular Cancer Therapeutics

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Functional role of CXCR4 in chronic myelogenous leukemia (CML) progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of extracellular signal-regulated kinase (Erk)-1/2, Akt, S6K, STAT3, and STAT5 prosurvival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with suboptimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperones and antiapoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. Bone marrow (BM) stromal cells (BMSC) markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BMSCs elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis, and decreased BCL6 levels in CML cells cocultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML-BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease. Mol Cancer Ther; 13(5); 1155-69. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

Beider

Darash-Yahana

Blaier

et al. 2014

Molecular Cancer Therapeutics

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“…These cells have also been used to screen methodologies or drugs that may inhibit HIV-1 infection or reduce transcriptional activation of the virus [117,[160][161][162][163][164][165][166][167][168][169][170][171][172][173]. These cell lines have also been used in studies of drug toxicity, permeability, and/or effects on cellular activation and differentiation to gain an understanding of what specific drugs might do to cells in the bone marrow [144,154,[174][175][176][177][178][179][180][181][182][183], as well as determining what signaling pathways may play a role or become dysregulated [184][185][186][187][188][189]. Additionally, other studies have been completed that utilize these cells to examine the role that distinct viral determinants as well as specific host factors have on cellular tropism, cellular differentiation, and cytopathology [190][191][192][193].…”

Section: Hl-60mentioning

confidence: 99%

“…These cells have been shown to retain CD4, CXCR4, and CCR5 expression and retain CD4 expression unless viral replication is active [138]. Given this observation, the HL-60 and OM-10.1 cell lines have been used in several studies that simply aim at examining the levels of CD4, CXCR4, and CCR5 or other surface markers under various cellular physiological conditions and drug treatments [138,[144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159]. These cells have also been used to screen methodologies or drugs that may inhibit HIV-1 infection or reduce transcriptional activation of the virus [117,[160][161][162][163][164][165][166][167][168][169][170][171][172][173].…”

Section: Hl-60mentioning

confidence: 99%

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

Nonnemacher¹,

Quiterio²,

Allen³

et al. 2017

Biology of Myelomonocytic Cells

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Human immunodeficiency virus type 1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), primarily infects T cells and cells of the monocyte-macrophage lineage. This is due to the presence of the cell surface receptor CD4 and the coreceptors, CXCR4, and CCR5. While the T-cell has classically been the cell type associated with HIV-1 disease progression, cells of the monocyte-macrophage lineage have also been shown to play a major role in this viral pathologic process. Classically, this has involved monocytic cells in the peripheral blood and tissue macrophages, however, over the course of HIV disease, the promyelomonocytic cells of the bone marrow (BM) have also been shown to play a role in pathogenesis retroviral disease in that they play an integral role in the reseeding of the periphery and end-organ tissues. This has involved an initial infection of the bone marrow hematopoietic progenitor cells. Given this observation, over the years there have been a number of cell lines that have been developed and provided valuable insights into research questions surrounding HIV-1 infection of the monocyte-macrophage cell lineage. In this regard, we will examine the biological and immunological properties of these BM-derived cell lines with respect to their utility in exploring the pathogenesis of HIV-1 in humans.

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“…A peptide inhibitor of the CXCR4 exhibited direct cytotoxicity against AML and multiple myeloma cells in vitro and in xenografts. Another CXCR4 inhibitor, AMD3100, worked synergistically with histone deacetylase inhibitor panobinostat to induce apoptosis of AML cells in vitro 120,121 . The AMD 3100 is a SDF-1α analogue known as plerixafor that is used in mobilizing normal progenitor cells into peripheral circulation 122 .…”

Section: Cxcr4mentioning

confidence: 99%

The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: A systematic review

Kupsa¹,

Horáček²,

Jebavý³

2015

BIOMED PAP

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Background. The treatment of malignancies like acute myeloid leukemia (AML) is often complicated by the heterogeneity of the disease and the mechanisms of the disease progression. This heterogeneity is often not reflected in standard treatment approaches which provide predictable outcomes in the majority of patients but fail in individual cases even with high-dose multi-agent chemotherapy regimens and allogeneic stem cell transplantation. Further, the unselective effect of chemotherapy causes high treatment-related toxicity and accelerates the risk of infection during prolonged pancytopenia, preventing further dose escalation. Despite rapid progress in therapeutic strategies, the fatality of high-grade malignancies remains enormous. Objectives. Adhesive interactions trigger signal transduction pathway activation and this prevents the apoptosis of both normal and malignant cells. A correlation between expression of defined adhesion molecules and patient outcome has been found for several malignant diseases including AML. We aim to describe how disruption of these signalling pathways can overcome the high resistance to treatment and increase the selectivity of targeting malignant cells. This could effectively reduce the overall treatment-related toxicity and improve the general outcome. Conclusions. Adhesion molecules facilitate growth of malignant diseases. This review provides a deeper insight into these processes. Modulation of adhesion molecules-mediated interactions is an innovative and feasible approach in treatment of AML and many other malignancies. Due to expected low toxicity it is an acceptable addition to standard chemotherapeutical regimens for all age groups of patients. This approach could improve the overall treatment outcome in the future.

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CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth

Cited by 84 publications

References 45 publications

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

Myelomonocytic Cell Lines in Modeling HIV-1 Infection of the Bone Marrow

The role of adhesion molecules in acute myeloid leukemia and (hemato)oncology: A systematic review

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