Toxic effects of AZD1208 on mouse oocytes and its possible mechanisms

Abstract

AZD1208, a pan-inhibitor that can effectively inhibit PIM kinase, is used for the treatment of advanced solid tumors and malignant lymphomas. Numerous studies have proved its curative effects while its potential cellular toxicity on reproduction was still little known. In this study, we investigated the toxic effects of AZD1208 on mouse oocytes. The results showed that AZD1208 treatment did not affect meiotic resumption, but postponed oocyte maturation as indicated by delayed first polar body extrusion. Further mechanistic study showed that AZD1208 treatment delayed spindle assembly. In addition, we found that oocytes treated with AZD1208 showed mitochondrial dysfunction. Abnormal mitochondrial clusters with decreased mitochondrial membrane potential were observed in oocytes during incubation in vitro. Moreover, increased oxidative stress was observed by testing the level of reactive oxygen species. In summary, our results suggest that AZD1208 treatment influences oocyte meiotic progression by causing mitochondrial dysfunctions and subsequent delayed spindle assembly.

The effects of microgravity on cellular elements of the central nervous system - astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte precursor cells

“…Similarly, a study using clinostat-simulated microgravity demonstrated that OPCs showed decreased proliferation and increased differentiation into astrocytes. The study also found changes in the expression of genes involved in the process of myelination [47,48].…”

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle

“…Previous studies using AZD1208 in vitro applied highly varying, but mostly micromolar, concentrations. Concentration-dependent effects in cell cultures have been examined with 10–40 µM (Park et al 2018 ; Yan et al 2022 ), 1–10 µM (Kreuz et al 2015 ; Harada et al 2015 ), but also from 1 nM to 3 µM (Trigg et al 2019 ). Experiments using single concentrations, again in cell cultures, often used concentrations from 1 to 5 µM (Kreuz et al 2015 ; Harada et al 2015 ; Cen et al 2014 ; Scarpa et al 2021 ).…”