Pang-Ting Cheng , Ho Lin , Yu-Chiao Cheng , Tzu-Hung Hsiao , Pei-Pei Jhan , Jia-Rung Tsai , Mei-Chih Chen , Tai-Lin Chen , Chieh-Lin Jerry Teng
{"title":"Alisertib通过抑制STAT3激活抑制急性髓系白血病细胞生长","authors":"Pang-Ting Cheng , Ho Lin , Yu-Chiao Cheng , Tzu-Hung Hsiao , Pei-Pei Jhan , Jia-Rung Tsai , Mei-Chih Chen , Tai-Lin Chen , Chieh-Lin Jerry Teng","doi":"10.1016/j.taap.2025.117449","DOIUrl":null,"url":null,"abstract":"<div><div>Aurora kinase A (AURKA) plays critical roles in the cell cycle. Its oncogenic functions have been identified in various types of cancer. However, its role in acute myeloid leukemia (AML) has not been extensively explored. Alisertib, a selective AURKA inhibitor, is currently being evaluated in clinical trials for the treatment of several cancers. In this study, we aimed to assess the efficacy of alisertib and elucidate its molecular mechanisms in AML cells. <em>In vitro</em> and <em>in vivo</em> experiments were conducted using western blotting and immunocytochemistry, respectively, to identify the effects of alisertib on two AML cell lines (KG-1 and MOLM-13). Primary cells from three patients with AML were used to examine the response to alisertib treatment. The results showed alisertib significantly reduced Thr288 phosphorylation of AURKA in both KG-1 and MOLM-13 cell lines. Interestingly, it selectively inhibited STAT3 phosphorylation at Tyr705, but not at Ser727. Notably, alisertib significantly decreased interleukin-6-induced nuclear pTyr705-STAT3 levels after short-term treatment, while also affecting the expression of downstream c-Myc. In addition to these <em>in vitro</em> findings, <em>in vivo</em> xenograft model using KG-1 cells showed significant tumor growth retardation accompanied by pTyr705-STAT3 inhibition following alisertib treatment. In primary AML patient cells, we observed a consistent trend in the alisertib-induced reduction of pTyr705-STAT3 and cell growth inhibition. In conclusion, AURKA and alisertib are promising therapeutic targets and treatment options for AML.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117449"},"PeriodicalIF":3.3000,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Alisertib inhibits acute myeloid leukemia cell growth by inhibiting STAT3 activation\",\"authors\":\"Pang-Ting Cheng , Ho Lin , Yu-Chiao Cheng , Tzu-Hung Hsiao , Pei-Pei Jhan , Jia-Rung Tsai , Mei-Chih Chen , Tai-Lin Chen , Chieh-Lin Jerry Teng\",\"doi\":\"10.1016/j.taap.2025.117449\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Aurora kinase A (AURKA) plays critical roles in the cell cycle. Its oncogenic functions have been identified in various types of cancer. However, its role in acute myeloid leukemia (AML) has not been extensively explored. Alisertib, a selective AURKA inhibitor, is currently being evaluated in clinical trials for the treatment of several cancers. In this study, we aimed to assess the efficacy of alisertib and elucidate its molecular mechanisms in AML cells. <em>In vitro</em> and <em>in vivo</em> experiments were conducted using western blotting and immunocytochemistry, respectively, to identify the effects of alisertib on two AML cell lines (KG-1 and MOLM-13). Primary cells from three patients with AML were used to examine the response to alisertib treatment. The results showed alisertib significantly reduced Thr288 phosphorylation of AURKA in both KG-1 and MOLM-13 cell lines. Interestingly, it selectively inhibited STAT3 phosphorylation at Tyr705, but not at Ser727. Notably, alisertib significantly decreased interleukin-6-induced nuclear pTyr705-STAT3 levels after short-term treatment, while also affecting the expression of downstream c-Myc. In addition to these <em>in vitro</em> findings, <em>in vivo</em> xenograft model using KG-1 cells showed significant tumor growth retardation accompanied by pTyr705-STAT3 inhibition following alisertib treatment. In primary AML patient cells, we observed a consistent trend in the alisertib-induced reduction of pTyr705-STAT3 and cell growth inhibition. In conclusion, AURKA and alisertib are promising therapeutic targets and treatment options for AML.</div></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":\"502 \",\"pages\":\"Article 117449\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X2500225X\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X2500225X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Aurora kinase A (AURKA) plays critical roles in the cell cycle. Its oncogenic functions have been identified in various types of cancer. However, its role in acute myeloid leukemia (AML) has not been extensively explored. Alisertib, a selective AURKA inhibitor, is currently being evaluated in clinical trials for the treatment of several cancers. In this study, we aimed to assess the efficacy of alisertib and elucidate its molecular mechanisms in AML cells. In vitro and in vivo experiments were conducted using western blotting and immunocytochemistry, respectively, to identify the effects of alisertib on two AML cell lines (KG-1 and MOLM-13). Primary cells from three patients with AML were used to examine the response to alisertib treatment. The results showed alisertib significantly reduced Thr288 phosphorylation of AURKA in both KG-1 and MOLM-13 cell lines. Interestingly, it selectively inhibited STAT3 phosphorylation at Tyr705, but not at Ser727. Notably, alisertib significantly decreased interleukin-6-induced nuclear pTyr705-STAT3 levels after short-term treatment, while also affecting the expression of downstream c-Myc. In addition to these in vitro findings, in vivo xenograft model using KG-1 cells showed significant tumor growth retardation accompanied by pTyr705-STAT3 inhibition following alisertib treatment. In primary AML patient cells, we observed a consistent trend in the alisertib-induced reduction of pTyr705-STAT3 and cell growth inhibition. In conclusion, AURKA and alisertib are promising therapeutic targets and treatment options for AML.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.