volasertib and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

Epidemiological studies of childhood leukemia survivors reveal an alarmingly high incidence of chronic health disabilities after treatment, therefore, more specific therapies need to be developed. Polo-like kinase 1 (Plk1) is a key player in mitosis and a target for drug development as it is upregulated in multiple cancer types. Small molecules targeting Plk1 are mainly ATP-competitors and, therefore, are known to elicit side effects due to lack of specificity. RNA interference (RNAi) is known for its high catalytic activity and target selectivity; however, the biggest barrier for its introduction into clinical use is its delivery. RNAi prodrugs are modified, self-delivering short interfering Ribonucleic Neutrals (siRNNs), cleaved by cytoplasmic enzymes into short interfering Ribonucleic Acids (siRNAs) once inside cells. In this study we aimed to investigate the potential of siRNNs as therapeutic tools in T-acute lymphoblastic leukemia (T-ALL) using T-ALL cell lines and patient-derived samples. We demonstrate for the first time that RNAi prodrugs (siRNNs) targeting Plk1, can enter pediatric T-ALL patient cells without a transfection reagent and induce Plk1 knockdown on both protein and mRNA levels resulting in G2/M-arrest and apoptosis. We also show that siRNNs targeting Plk1 generate less toxicity in normal cells compared to the small molecule Plk1 inhibitor, BI6727, suggesting a potentially good therapeutic index.

Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Child; Drug Delivery Systems; G2 Phase Cell Cycle Checkpoints; Gene Knockdown Techniques; Gene Silencing; Humans; M Phase Cell Cycle Checkpoints; Polo-Like Kinase 1; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; RNA Interference; RNA, Messenger; RNA, Small Interfering