Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells

LIGHT (HVEM-L, TNFSF14, or CD258), an entity homologous to lymphotoxins, with inducible nature and the ability to compete with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM)/tumor necrosis factor (TNF)-related 2, is a member of the TNF superfamily. It is expressed as a homotrimer on activated T cells and dendritic cells (DCs), and has three receptors: HVEM, LT-β receptor (LTβR), and decoy receptor 3 (DcR3). So far, three receptors with distinct cellular expression patterns are known to interact with LIGHT. Follicular DCs and stromal cells bind LIGHT through LTβR. We monitored the effects of LIGHT on human bone marrow-derived mesenchymal stem cells (BM-MSCs). At first, we checked the negative and positive differentiation markers of BM-MSCs. And we confirmed the quality of MSCs by staining cells undergoing adipogenesis (Oil Red O staining), chondrogenesis (Alcian blue staining), and osteogenesis (Alizarin red staining). After rhLIGHT treatment, we monitored the count, viability, and proliferation of cells and cell cycle distribution. PDGF and TGFβ production by rhLIGHT was examined by ELISA, and the underlying biological mechanisms were studied by immunoblotting by rhLIGHT treatment. LTβR was constitutively expressed on the surface of human BM-MSCs. Cell number and viability increased after rhLIGHT treatment. BM-MSC proliferation was induced by an increase in the S/G2/M phase. The expression of not only diverse cyclins such as cyclin B1, D1, D3, and E, but also CDK1 and CDK2, increased, while that of p27 decreased, after rhLIGHT treatment. RhLIGHT-induced PDGF and TGFβ production mediated by STAT3 and Smad3 activation accelerated BM-MSC proliferation. Thus, LIGHT and LTβR interaction increases the survival and proliferation of human BM-MSCs, and therefore, LIGHT might play an important role in stem cell therapy.

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“…They were washed three times with ice-cold PBS and then harvested. Western blotting was performed as previously described [34]. …”

Section: Methodsmentioning

confidence: 99%

“…Microarray data analysis was performed as previously described [34]. Expression changes of >2-fold were considered significant.…”

Section: Methodsmentioning

confidence: 99%

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

et al. 2016

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“…Kasumi-1 cells were incubated with 0, 1, 2, and 5 mM radotinib for 48 h at 37°C, followed by harvesting and washing twice with phosphate buffered saline (PBS). The MTS assay was performed using the CellTiter 96 solution, as described previously, 22,23 and cell viability was assessed using the MuseÒ viability assay kit (Merck Millipore), according to the manufacturer's instructions. Samples were analyzed using MuseÒ cell analyzer and its associated software.…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…21 Previously, we presented that radotinib increased cytotoxicity of all types of AML cells. 22,23 It inhibited AML cell proliferation by activating mitochondria-dependent apoptosis and inducing the expression of CDK inhibitors. 22 Moreover, radotinib induced apoptosis in CD11b + cells differentiated from AML blast cells.…”

Section: Introductionmentioning

confidence: 99%

Radotinib inhibits mitosis entry in acute myeloid leukemia cells via suppression of Aurora kinase A expression

et al. 2019

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Aurora kinases play critical roles in regulating several processes pivotal for mitosis. Radotinib, which is approved in South Korea as a second-line treatment for chronic myeloid leukemia, inhibits the tyrosine kinase BCR-ABL and plateletderived growth factor receptor. However, the effects of radotinib on Aurora kinase expression in acute myeloid leukemia are not well studied. Interestingly, the cytotoxicity of acute myeloid leukemia cells was increased by radotinib treatment. Radotinib significantly decreased the expression of cyclin-dependent kinase 1 and cyclin B1, the key regulators of G2/M phase, and inhibited the expression of Aurora kinase A and Aurora kinase B in acute myeloid leukemia cells. In addition, radotinib decreased the expression and binding between p-Aurora kinase A and TPX2, which are required for spindle assembly. Furthermore, it reduced Aurora kinase A and polo-like kinase 1 phosphorylation and suppressed the expression of a-, band nd g-tubulin in acute myeloid leukemia cells. Furthermore, radotinib significantly suppressed the key regulators of G2/M phase including cyclin B1 and Aurora kinase A in a xenograft animal model. Therefore, our results suggest that radotinib can abrogate acute myeloid leukemia cell growth both in vitro and in vivo and may serve as a candidate agent or a chemosensitizer for treating acute myeloid leukemia.

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“…were approved by the Ethics Committee and Institutional Review Board of the Ulsan University Hospital (UUH-IRB- [11][12][13][14][15][16][17][18]. All procedures involving animals were in accordance with the Laboratory Animals Welfare Act, the Guide for the Care and Use of Laboratory Animals, and the Guidelines and Policies for Rodent Experimentation provided by the Institutional Animal Care and Use Committee of the Ulsan University of Korea (Approval No.…”

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confidence: 99%

Radotinib Enhances Cytarabine (Ara-C)-Induced Acute Myeloid Leukemia Cell Death

Heo

Noh

Kim

et al. 2020

Preprint

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Background: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death and cell cycle distribution in AML cells. Methods: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. We also confirmed synergistic effects of radotinib and Ara-C on the xenograft model in vivo. Results: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

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Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells

Cited by 23 publications

References 30 publications

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

LIGHT (TNFSF14) Increases the Survival and Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells

Radotinib inhibits mitosis entry in acute myeloid leukemia cells via suppression of Aurora kinase A expression

Radotinib Enhances Cytarabine (Ara-C)-Induced Acute Myeloid Leukemia Cell Death

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