RNAi prodrugs decrease elevated mRNA levels of Polo-like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients.

Autor: Kolosenko I; Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Goroshchuk O; Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Vidarsdottir L; Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Björklund AC; Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Dowdy SF; Department of Cellular & Molecular Medicine, UCSD School of Medicine, La Jolla, CA, USA., Palm-Apergi C; Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 May; Vol. 35 (5), pp. e21476.
DOI: 10.1096/fj.202002454RR
Abstrakt: 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.
(© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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