Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin <scp>type‐B</scp> receptor 4

Ma, Weina; Zhu, Man; Wang, Bo; Gong, Zhengyan; Du, Xia; Yang, Tianfeng; Shi, Xianpeng; Dai, Bingling; Zhan, Yingzhuan; Zhang, Dongdong; Ji, Yanhong; Wang, Yan; Li, Song; Zhang, Yanmin

doi:10.1002/1878-0261.13270

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…7-Ketocholesterol is an oxidized cholesterol derivative that improves vincristine and doxorubicin cytotoxicity through a classical MDR-regulated mechanism in CML ( 38 ). Vandetanib, an oral multiple tyrosine kinase Inhibitor (TKI), inhibits acute myeloid leukemia cells proliferation and overcomes IM resistance in CML by targeting ephrin type-B receptor 4 (EPHB4) ( 39 ). In the present study, compared with K562 cells, K/G cells exhibited greater IM resistance.…”

Section: Discussionmentioning

confidence: 99%

NDRG3 regulates imatinib resistance by promoting β‑catenin accumulation in the nucleus in chronic myelogenous leukemia

Wang,

Simin,

Sun

et al. 2023

Oncol Rep

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Imatinib resistance in chronic myelogenous leukemia (CML) is a clinical problem. The present study examined the role of N-Myc downstream regulatory gene 3 (NDRG3) in imatinib resistance in CML. Quantitative PCR demonstrated that NDRG3 was highly expressed in patients with CML. Cell Counting Kit (CCK)-8 experiments proved that NDRG3 promoted the proliferation of K562 CML cells and enhanced imatinib resistance. Dual-luciferase assay showed that microRNA (miR)-204-5p inhibited expression of NDRG3 and immunofluorescence experiments showed that NDRG3 promoted accumulation of β-catenin in the nucleus, thereby increasing the expression of downstream drug resistance- and cell cycle-associated factors (c-Myc and MDR1). At the same time, cell proliferation experiments showed that β-catenin played a role in cell proliferation and drug resistance. Co-transfection with small interfering (si)-β-catenin partially reversed the effect of NDRG3. This finding indicated that NDRG3 plays an important role in imatinib resistance and miR-204-5p and β-catenin are involved in the biological behavior of NDRG3. The present results provide theoretical support for overcoming drug resistance in CML.

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Section: Discussionmentioning

confidence: 99%

NDRG3 regulates imatinib resistance by promoting β‑catenin accumulation in the nucleus in chronic myelogenous leukemia

Wang,

Simin,

Sun

et al. 2023

Oncol Rep

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“…After 4 days, MTS and PMS were added to the cell culture and incubated at 37°C for 2–3 h. The absorbance was measured at 490 nm to quantify the viable cells. The growth ratio of treated cells was calculated by comparing the absorbance to the non-treated cells ( Ma et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Synthesis, characterization, and anti-cancer potential of novel p53-mediated Mdm2 and Pirh2 modulators: an integrated In silico and In vitro approach

Niazi,

Kavana,

Aishwarya

et al. 2024

Front. Chem.

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Introduction: Leukemia is a global health concern that requires alternative treatments due to the limitations of the FDA-approved drugs. Our focus is on p53, a crucial tumor suppressor that regulates cell division. It appears possible to stabilize p53 without causing damage to DNA by investigating dual-acting inhibitors that target both ligases. The paper aims to identify small molecule modulators of Mdm2 and Pirh2 by using 3D structural models of p53 residues and to further carry out the synthesis and evaluation of hit candidates for anti-cancer potency by in vitro and in silico studies.Methods: We synthesized structural analogues of MMs02943764 and MMs03738126 using a 4,5-(substituted) 1,2,4-triazole-3-thiols with 2-chloro N-phenylacetamide in acetone with derivatives of PAA and PCA were followed. Cytotoxicity assays, including MTT, Trypan Blue Exclusion, and MTS assays, were performed on cancer cell lines. Anti-proliferation activity was evaluated using K562 cells. Cell cycle analysis and protein expression studies of p53, Mdm2, and Pirh2 were conducted using flow cytometry.Results: As for results obtained from our previous studies MMs02943764, and MMs03738126 were selected among the best-fit hit molecules whose structural analogues were further subjected to molecular docking and dynamic simulation. Synthesized compounds exhibited potent anti-proliferative effects, with PAC showing significant cytotoxicity against leukemia cells. PAC induced cell cycle arrest and modulated p53, Mdm2, and Pirh2 protein expressions in K562 cells. Molecular docking revealed strong binding affinity of PAC to p53 protein, further confirmed by molecular dynamics simulation.Discussion: The study presents novel anticancer compounds targeting the p53 ubiquitination pathway, exemplified by PAC. Future perspectives involve further optimization and preclinical studies to validate PAC’s potential as an effective anticancer therapy.

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“…The combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib-resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via EPHB4 targeting [177]. Apart from the setting of drug resistance, a highly specific mAb against EPHB4 (MAb131) was shown to be effective against AML in vitro and in vivo, rendering EPHB4 a potential therapeutic target for the subset of AML cases with high EPHB4 expression [146].…”

Section: Eph/ephrin Therapeutic Targeting In Hematologic Malignanciesmentioning

confidence: 98%

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets

Stergiou,

Papadakos,

Karyda

et al. 2023

Cancers

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Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

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Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type‐B receptor 4

Cited by 5 publications

References 44 publications

NDRG3 regulates imatinib resistance by promoting β‑catenin accumulation in the nucleus in chronic myelogenous leukemia

NDRG3 regulates imatinib resistance by promoting β‑catenin accumulation in the nucleus in chronic myelogenous leukemia

Synthesis, characterization, and anti-cancer potential of novel p53-mediated Mdm2 and Pirh2 modulators: an integrated In silico and In vitro approach

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets

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