Combined application of arsenic trioxide and lithium chloride augments viability reduction and apoptosis induction in human rhabdomyosarcoma cell lines

Abstract

Rhabdomyosarcomas (RMS) are the most prevalent soft tissue sarcomas affecting children and adolescents. Despite intensive treatment consisting of multimodal chemotherapy and surgery RMS patients diagnosed with metastatic disease expect long term survival rates of only 20%. Often multidrug resistance arises upon initial response emphasizing the need for new therapeutic drugs to improve treatment efficiency. Previously, we demonstrated the efficacy of the FDA approved drug arsenic trioxide (ATO) specifically inhibiting viability and clonal growth as well as inducing cell death in human RMS cell lines of different subtypes. In this study, we combined low dose ATO with lithium chloride (LiCl), which is approved as mood stabilizer for the treatment of bipolar disorder, but also inhibits growth and survival of different cancer cell types in pre-clinical research. Indeed, we could show additive effects of LiCl and ATO on viability reduction, decrease of colony formation as well as cell death induction. In the course of this, LiCl induced inhibitory glycogen synthase kinase-3β (GSK-3β) serine 9 phosphorylation, whereas glioma associated oncogene family 1 (GLI1) protein expression was particularly reduced by combined ATO and LiCl treatment in RD and RH-30 cell lines, showing high rates of apoptotic cell death. These results imply that combination of ATO with LiCl or another drug targeting GSK-3 is a promising strategy to enforce the treatment efficiency in resistant and recurrent RMS.

Multiplexed quantitative screens of single cell shape and YAP/TAZ localisation identify DOCK5 as a coincident detector of polarity and adhesion during migration

“…6e). Further, we confirmed LiCl was working effectively by observing a significant increase in whole cell β-catenin levels via immunofluorescence (Supplementary Figure 4c, d) as previous studies have shown that LiCl-induced GSK3β phosphorylation results in β-catenin stabilisation[103][104][105][106] , .…”

Synergistic anti-tumor effects of arsenic trioxide and blue LED irradiation on human osteosarcoma

“…Synergistic combination effects of ATO and fibroblast growth factor receptor inhibitor has been shown in squamous cell lung carcinoma 23. And combination with lithium chloride (LiCl) showed reduction in cell viability reduction colony formation, and cell death in rhabdomyosarcomas (RMS) 24. ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) achieves effective treatment in pancreatic ductal adenocarcinoma 25.…”

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

“…In addition, the dual inhibition of GLI1/2 and Hh-related protein smoothened (SMO) or glycogen synthase kinase 3 (GSK3) led to a significant reduction in colony formation in both ARMS and ERMS cells. However, 3D-spheroid culture, as a better representation of the in vivo situation, showed limited additive effects of these combinations (52,53). The current in vitro and in vivo models do not allow for direct translation of these combinations to a clinical setting.…”