Testing of the survivin suppressant YM155 in a large panel of drug-resistant neuroblastoma cell lines

Michaelis, M.; Voges, Y.; Rothweiler, F.; Weipert, F.; Zhia-Amad, A.; Cinatl, J.; von Deimling, A.; Westermann, F.; Roedel, F.; Wass, M. N.

doi:10.1101/2020.01.27.921312

bioRxiv · 10.1101/2020.01.27.921312

Testing of the survivin suppressant YM155 in a large panel of drug-resistant neuroblastoma cell lines

Michaelis, M.·Voges, Y.·Rothweiler, F.·Weipert, F.·Zhia-Amad, A.·Cinatl, J.·von Deimling, A.·Westermann, F.·Roedel, F.·Wass, M. N.

View original source ↗Export metadata ↓

Abstract

The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.

Source connections

Published article ↗

Explore related subjects

pharmacology and toxicology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Michaelis, M., Voges, Y., Rothweiler, F., Weipert, F., Zhia-Amad, A., Cinatl, J., von Deimling, A., Westermann, F., Roedel, F., Wass, M. N.. 2020-01-28. Testing of the survivin suppressant YM155 in a large panel of drug-resistant neuroblastoma cell lines. https://doi.org/10.1101/2020.01.27.921312

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗

bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

bioRxiv2020

Elucidating Direct Kinase Targets of Compound Danshen Dropping Pills Employing Archived Data and Prediction Models

The research on the direct target of traditional Chinese medicine (TCM) is the key to study the mechanism and material basis of TCM, but there is still no effective technical methods at present. For Compound Danshen dropping pills (CDDP), there is no report about its direct targets. In this study, the direct targets of CDDP were studied for the first time, especially focusing on the protein kinase family, which plays causal roles in a variety of human disease. Firstly, the literature database of CDDP was constructed by literature retrieval, and the important components contained in CDDP were extracted. Secondly, the potential direct targets of important components was obtained through querying public database and predicted by Multi-voting SEA algorithm. Then, the KinomeX system was used to predict and to filter the potential kinase targets of CDDP. Finally, the experimental verification was carried out. In total, 30 active kinase targets was obtained at 25 g/ml concentration of CDDP, and 9 dose-dependent targets were obtained at 250 g/ml concentration of CDDP. This is an efficient and accurate strategy by integrating the targets recorded in several public databases and the targets calculated by two in silico modelling approaches predict potential direct targets of TCM, which can lay an important foundation for the study of the mechanism and material basis of them, promoting the modernization of TCM.

pharmacology and toxicology↗