Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia

by Selleckchem | Mar 07 2023

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Comments：

This study evaluated the potential use of pitavastatin, a drug currently used to treat high cholesterol, as a treatment strategy for B-cell acute lymphoblastic leukemia (ALL) that has become resistant to standard chemotherapy. The study found that pitavastatin was able to inhibit the proliferation of both parental and vincristine-resistant REH tumor cells, and it significantly decreased cell viability in the vincristine-resistant ALL cells compared to the parental control in a co-culture model.

Furthermore, in an in vivo model using NSG mice, pitavastatin was shown to significantly reduce the number of human CD45+ REH ALL cells in the bone marrow after 4 weeks of treatment, with mechanistic studies indicating that pitavastatin treatment led to apoptosis in the vincristine-resistant cells.

Overall, the study suggests that pitavastatin may have potential as a repurposed chemotherapeutic agent for vincristine-resistant B-cell ALL. However, further research is needed to validate these findings and to determine the optimal dose, duration, and safety of pitavastatin for this indication.