A novel dimeric CXCR4 antagonist synergizes with chemotherapy in acute myeloid leukaemia by mobilizing leukaemic cells from their associated bone marrow niches

Huang, Yazi; Huang, Ziwei; An, Jing; Xu, Yixin

doi:10.1111/bjh.16127

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…Huang et al focused on this CXCR4/SDF-1α interaction and found that the addition of a CXCR4 peptide antagonist to cytarabine, which is used in conventional chemotherapy in leukemia, has a synergistic effect on AML treatment. This has now emerged as one of the candidates to eradicate residual disease and overcome chemoresistance in AML [56].…”

Section: Leukemic Bone Marrow Niche and Chemotherapymentioning

confidence: 99%

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

Yokota

Kawamoto

Gaowa

et al. 2021

IJMS

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Leukemia is a hematological malignancy that originates from hematopoietic stem cells in the bone marrow. Significant progress has made in understanding its pathogensis and in establishing chemotherapy and hematopoietic stem cell transplantation therapy (HSCT). However, while the successive development of new therapies, such as molecular-targeted therapy and immunotherapy, have resulted in remarkable advances, the fact remains that some patients still cannot be saved, and resistance to treatment and relapse are still problems that need to be solved in leukemia patients. The bone marrow (BM) niche is a microenvironment that includes hematopoietic stem cells and their supporting cells. Leukemia cells interact with bone marrow niches and modulate them, not only inducing molecular and functional changes but also switching to niches favored by leukemia cells. The latter are closely associated with leukemia progression, suppression of normal hematopoiesis, and chemotherapy resistance, which is precisely the area of ongoing study. Exosomes play an important role in cell-to-cell communication, not only with cells in close proximity but also with those more distant due to the nature of exosomal circulation via body fluids. In leukemia, exosomes play important roles in leukemogenesis, disease progression, and organ invasion, and their usefulness in the diagnosis and treatment of leukemia has recently been reported. The interaction between leukemia cell-derived exosomes and the BM microenvironment has received particular attention. Their interaction is believed to play a very important role; in addition to their diagnostic value, exosomes could serve as a marker for monitoring treatment efficacy and as an aid in overcoming drug resistance, among the many problems in leukemia patients that have yet to be overcome. In this paper, we will review bone marrow niches in leukemia, findings on leukemia-derived exosomes, and exosome-induced changes in bone marrow niches.

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Section: Leukemic Bone Marrow Niche and Chemotherapymentioning

confidence: 99%

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

Yokota

Kawamoto

Gaowa

et al. 2021

IJMS

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“…So beschäftigt sich ein kleinerer Forschungszweig mit der Entwicklung von dimeren und oligomeren Strukturen, welche durch zwei oder mehr reaktive Zentren charakterisiert sind. Ein Beispiel hierfür ist das im Jahr 2019 präklinisch evaluierte HC4319, welches die Strukturmotive DV1 und DV3 des exogenen Liganden vMIP-II C-terminal peptidisch verknüpft aufgreift [60].…”

Section: Auf Der Suche Nach Wirkstoffendie Entwicklung Von Cxcr4-ligandenunclassified

Der Chemokinrezeptor CXCR4 – seine Entwicklung und Bedeutung in der nuklearmedizinischen Theranostik

Bergner

Gummesson

Joksch

et al. 2021

Der Nuklearmediziner

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ZusammenfassungDer Chemokinrezeptor CXCR4 – häufig nachgewiesen, doch selten greifbar. Während in einer schier endlosen Zahl an Studien seine physiologische und pathogene Präsenz, seine zellulären Funktionen sowie Möglichkeiten seiner gezielten pharmakologischen Kontrolle seit fast 30 Jahren erforscht werden, ist das Spektrum seiner nuklearmedizinischen klinischen Anwendungen mit malignen Krankheitsbildern des hämatopoetischen Systems und einigen wenigen Entzündungsprozessen immer noch überschaubar. Das Verständnis um Prozesse, die seine dynamische Zelloberflächenexpression regulieren sowie die Suche nach selektiven Radiopharmaka zur Unterscheidung physiologischer von pathogenen CXCR4-Expressionen stellen die Herausforderung der Zukunft dar, um den CXCR4 als ein vielseitiges theranostisches Target in der Nuklearmedizin zu manifestieren.

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“…LY2510924 was also in clinical trials for treating multiple diseases such as solid tumors, acute myeloid leukemia (AML), extensive-disease small cell lung cancer (ED-SCLC), and advanced cancer [ 29 , 30 , 38–42 ]. Other compounds used in this study were in the preclinical stage, including linear L- and D-peptides derived from vMIP-II, shown by our laboratories to bind CXCR4 and to have potent activity in animal models of AML and hematopoietic stem cells mobilization [ 43 , 44 ]. Additionally, small molecule IT1t effectively blocks X4-tropic HIV infection via CXCR4 with an IC 50 of 7 nM and reduces inflammation in mice [ 31 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

Meng,

Zhu,

Mao

et al. 2023

Bioscience Reports

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The chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The results were rationalized by molecular modeling of CXCR4–antagonist interactions from which the common as well as different receptor binding sites of these antagonists were derived, revealing a number of important residues such as W94, D97, H113, D171, D262, and E288, mostly of negative charge. To further examine this finding, we designed and synthesized new antagonistic analogs by adding positively charged residues Arg to a D-peptide template to enhance the postulated charge–charge interactions. The newly designed analogs displayed significantly increased binding to CXCR4, which supports the notion that negatively charged residues of CXCR4 can engage in interactions with moieties of positive charge of the antagonistic ligands. The results from these mutational, modeling and new analog design studies shed new insight into the molecular mechanisms of different types of antagonists in recognizing CXCR4 and guide the development of new therapeutic agents.

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A novel dimeric CXCR4 antagonist synergizes with chemotherapy in acute myeloid leukaemia by mobilizing leukaemic cells from their associated bone marrow niches

Cited by 6 publications

References 9 publications

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

Remodeling of Bone Marrow Niches and Roles of Exosomes in Leukemia

Der Chemokinrezeptor CXCR4 – seine Entwicklung und Bedeutung in der nuklearmedizinischen Theranostik

Biological and mutational analyses of CXCR4–antagonist interactions and design of new antagonistic analogs

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