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RNAi prodrugs decrease elevated mRNA levels of Polo-like kinase 1 in ex vivo cultured primary cells from pediatric
Iryna Kolosenko1, Oksana Goroshchuk1, Linda Vidarsdottir1
1Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Abstract:
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.
Insights
Targeting Polo-like kinase 1 (Plk1) with RNA interference (RNAi) prodrugs effectively reduces elevated Plk1 levels in pediatric acute myeloid leukemia (AML) cells. This approach also enhances the efficacy of chemotherapy, offering a promising strategy for treating pediatric AML.
Area of Science:
- Molecular Biology
- Oncology
- Gene Therapy
Background:
- Polo-like kinase 1 (Plk1) is a key cell cycle regulator frequently overexpressed in various cancers, including acute myeloid leukemia (AML).
- Pediatric AML patients face poor prognoses and long-term treatment side effects, highlighting the need for novel therapeutic strategies.
- Existing Plk1 inhibitors have shown limited success in clinical trials due to adverse reactions.
Purpose of the Study:
- To investigate the efficacy of PLK1-targeting RNA interference (RNAi) prodrugs in pediatric AML.
- To assess the selective downregulation of Plk1 in primary pediatric AML cells.
- To determine if Plk1 inhibition can potentiate the effects of standard chemotherapy in pediatric AML.
Main Methods:
- Utilized PLK1-targeting RNA interference (RNAi) prodrugs for selective delivery into primary cells without transfection reagents.
- Quantified Plk1 and PLK4 mRNA expression levels in pediatric AML patients compared to healthy donors.
- Assessed the impact of RNAi prodrugs on Plk1 expression and other PLK family members.
- Evaluated the combined effect of Plk1 downregulation and cytarabine treatment on pediatric AML cells.
Main Results:
- Pediatric AML patients exhibit significantly higher mRNA expression of PLK1 and PLK4 compared to healthy individuals.
- RNAi prodrugs achieved an average 50% downregulation of Plk1 in pediatric AML cells, with minimal impact on other PLK family members.
- The decrease in Plk1 levels induced by RNAi prodrugs potentiated the anti-leukemic effect of cytarabine.
Conclusions:
- PLK1-targeting RNAi prodrugs represent a viable strategy to reduce elevated Plk1 levels in pediatric AML.
- This RNAi-based approach can sensitize pediatric AML cells to conventional chemotherapeutics, potentially improving treatment outcomes.
- Selective Plk1 inhibition via RNAi prodrugs offers a promising therapeutic avenue for pediatric AML, addressing limitations of current treatments.
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