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RNAi prodrugs decrease elevated mRNA levels of Polo‐like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients
Author(s) -
Kolosenko Iryna,
Goroshchuk Oksana,
Vidarsdottir Linda,
Björklund AnnCharlotte,
Dowdy Steven F.,
PalmApergi Caroline
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002454rr
Subject(s) - plk1 , cytarabine , myeloid leukemia , prodrug , rna interference , leukemia , cancer research , medicine , ex vivo , myeloid , kinase , pharmacology , biology , in vivo , cell cycle , cancer , microbiology and biotechnology , rna , biochemistry , gene
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.