title: Molecular targeting of the oncoprotein PLK1 in pediatric acute myeloid leukemia: RO3280, a novel PLK1 inhibitor, induces apoptosis in leukemia cells.
abstract: Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor; however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35; p < 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy; however, the underlying mechanisms remain to be determined.
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. wangnn90s@163.com.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Wang
authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. szlizhiheng@hotmail.com.
authors.forename: Zhi-Heng
authors.initials: ZH
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. huitingzhousdfey@163.com.
authors.forename: He
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. taoyanfang1982@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. xulixiao2013@hotmail.com.
authors.forename: Li-Xiao
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. drlujun_sz@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. cl2012@sohu.com.
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authors.affiliation: Department of Gastroenterology, the 5th Hospital of Chinese People's Liberation Army (PLA), Yinchuan 750000, China. du_xiaojuan123@163.com.
authors.forename: Xiao-Juan
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authors.affiliation: Department of Cell and Molecular Biology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, China. sunlichao_1980@hotmail.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. wenlizhao69@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. xiaopfdr@gmail.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. baseff77@gmail.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. sky2skeleton@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. ray8302880@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. ligangmailbox@hotmail.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. ray8302880@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. huitingzhousdfey@163.com.
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authors.affiliation: Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215003, China. flykf@163.com.
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mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000737:chemistry / Q000633:toxicity*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D000097869:Polo-Like Kinase 1
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000097869:Polo-Like Kinase 1; C000601179:RO3280