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

Heo, Sook-Kyoung; Noh, Eui-Kyu; Jeong, Yoo Kyung; Ju, Lan Jeong; Sung, Jun Young; Cheon, Jaekyung; Koh, Su‐Jin; Min, Young Joo; Choi, Yun Suk; Jo, Jae‐Cheol

doi:10.1177/1010428319848612

Cited by 13 publications

(10 citation statements)

References 44 publications

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“…However, the expression level of p53 and p21 increased after PYP treatment. Heo et al . showed that radotinib, a chemosensitizer and candidate agent, could decrease the expression of CDK1 and Cyclin B1, the key regulators of G2/M phase, in acute myeloid leukemia cells and a xenograft animal model.…”

Section: Resultsmentioning

confidence: 99%

“…However, the expression level of p53 and p21 increased after PYP treatment. Heo et al 60 showed that radotinib, a chemosensitizer and candidate agent, could decrease the expression of CDK1 and Cyclin B1, the key regulators of G2/M phase, in acute myeloid leukemia cells and a xenograft animal model. Luo et al 61 reported that excessive sodium fluoride intake caused the G2/M phase arrest in renal cells and in a mouse model, with this being accompanied by the up-regulation of p21 and p53, as well as the down-regulation of CyclinB1 and CDK1.…”

Section: Effect Of Porphyrans On Gene Expression Of the Cell Cycle Inmentioning

confidence: 99%

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Antitumor bioactivity of porphyran extracted from Pyropia yezoensis Chonsoo2 on human cancer cell lines

Yan

et al. 2019

J Sci Food Agric

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BACKGROUND Pyropia yezoensis, rich in porphyran, is a medicine‐edible red alga. In the present study, the physicochemical characteristics, conformational states and antitumor activities of a novel porphyran extracted from the high‐yield algal strain Pyropia yezoensis Chonsoo2 and its two degraded derivatives by gamma irradiation were investigated. RESULTS Pyropia yezoensis porphyran is a water‐soluble, triple‐helical sulfated hetero‐galactopyranose, named PYP. PYP was degraded by gamma irradiation at 20 kGy and 50 kGy, giving two low molecular weight derivatives comprising PYP‐20 and PYP‐50, respectively. PYP with a higher molecular weight has a solution conformation different from PYP‐20 and PYP‐50. Three porphyrans had no toxicity in normal human liver cells (HL‐7702) and showed antitumor effects on Hep3B, HeLa and MDA‐MB‐231. They had better antitumor against HeLa cells, exhibiting a similar inhibition ratio compared to 5‐fluorouracil, with PYP especially exhibiting a higher inhibition ratio than 5‐fluorouracil. With respect to HeLa cells, the different antitumor activities might be related to porphyran molecular weight and solution conformation. Furthermore, the HeLa cell cycle was blocked in the G2/M phase after PYP treatment, leading to cell proliferation inhibition. The induction of cell cycle arrest was related to the changes in the expression of p21, p53, Cyclin B1 and cyclin‐dependent kinase 1. CONCLUSION Pyropia yezoensis porphyran, as applied to medicine and functional food, could potentially be used as a non‐toxic natural adjuvant in cancer therapy. © 2019 Society of Chemical Industry

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Section: Resultsmentioning

confidence: 99%

Section: Effect Of Porphyrans On Gene Expression Of the Cell Cycle Inmentioning

confidence: 99%

Antitumor bioactivity of porphyran extracted from Pyropia yezoensis Chonsoo2 on human cancer cell lines

Yan

et al. 2019

J Sci Food Agric

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“…Radotinib also acts as a CDK inhibitor, which strongly inhibits AML cell proliferation [17]. Alternatively, it functions as an AURKA inhibitor, which suppresses the expression of AURKA and related proteins including Bora, polo-like kinase 1, and TPX2 [34]. Moreover, radotinib induces apoptosis directly in cells differentiated from AML blasts [16].…”

Section: Discussionmentioning

confidence: 99%

Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

et al. 2020

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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 in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. 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. 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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“…Furthermore, radotinib induced solid cancer cell death via activation of natural killer cell cytotoxicity [ 22 ]. In our previous study, radotinib induced apoptosis in various acute myeloid leukemia (AML) cells [ 23 – 25 ]. In particular, targeting c-KIT by radotinib promoted cell death in c-KIT-positive AML cells, and this mechanism was similar to that of dasatinib in AML cells [ 19 , 20 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study, radotinib induced apoptosis in various acute myeloid leukemia (AML) cells [ 23 – 25 ]. In particular, targeting c-KIT by radotinib promoted cell death in c-KIT-positive AML cells, and this mechanism was similar to that of dasatinib in AML cells [ 19 , 20 , 25 ]. Additionally, radotinib enhanced cytarabine-induced AML cell death in vitro and in vivo [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Radotinib inhibits multiple myeloma cell proliferation via suppression of STAT3 signaling

et al. 2022

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Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.

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

Cited by 13 publications

References 44 publications

Antitumor bioactivity of porphyran extracted from Pyropia yezoensis Chonsoo2 on human cancer cell lines

Antitumor bioactivity of porphyran extracted from Pyropia yezoensis Chonsoo2 on human cancer cell lines

Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

Radotinib inhibits multiple myeloma cell proliferation via suppression of STAT3 signaling

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