RNAi prodrugs decrease elevated mRNA levels of Polo‐like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients
| Autor: | Steven F. Dowdy, Ann-Charlotte Björklund, Caroline Palm-Apergi, Iryna Kolosenko, Linda Vidarsdottir, Oksana Goroshchuk |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Apoptosis Cell Cycle Proteins Protein Serine-Threonine Kinases Biochemistry 03 medical and health sciences 0302 clinical medicine Cell Movement RNA interference Proto-Oncogene Proteins hemic and lymphatic diseases Biomarkers Tumor Tumor Cells Cultured Genetics medicine Humans Prodrugs RNA Messenger Child Protein Kinase Inhibitors Molecular Biology Cell Proliferation Kinase business.industry Tumor Suppressor Proteins Cell Cycle Myeloid leukemia Transfection Cell cycle Prognosis Gene Expression Regulation Neoplastic Leukemia Myeloid Acute 030104 developmental biology Case-Control Studies Cancer cell Cytarabine Cancer research RNA Interference business 030217 neurology & neurosurgery Ex vivo Biotechnology medicine.drug |
| Zdroj: | The FASEB Journal. 35 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.202002454rr |
| Popis: | Polo-like kinase 1 (Plk1) is an important regulator of the cell cycle and it is frequently overexpressed in cancer cells. Several small molecule inhibitors have been developed to target Plk1 and some of them have reached clinical trials in adults with acute myeloid leukemia (AML). Pediatric AML patients have a poor prognosis and survivors suffer from long-term side effects. As adult AML cells have an elevated expression of Plk1, AML is a disease candidate for Plk1 inhibition. However, the relative success of clinical trials have been hampered by adverse reactions. Herein, PLK1-targeting RNA interference (RNAi) prodrugs that enter cells without a transfection reagent are used to target PLK1 selectively in primary cells from pediatric AML patients. We show that PLK1 and PLK4 mRNA expression are significantly higher in pediatric AML patients when compared to healthy donors and that PLK1 is downregulated by on average 50% using RNAi prodrugs without a significant effect on other PLK family members. In addition, the RNAi prodrug-induced decrease in PLK1 can be used to potentiate the effect of cytarabine. In summary, PLK1-targeting RNAi prodrugs can decrease the elevated levels of PLK1 in primary cells from pediatric AML patients and sensitize pediatric AML cells to chemotherapeutics. |
| Databáze: | OpenAIRE |
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