Rhabdomyosarcoma (RMS) accounts for up to 10% of childhood cancers and nearly half of pediatric soft tissue sarcomas. While multimodal therapies have improved outcomes for low- and intermediate-risk patients, high-risk or metastatic cases still suffer poor survival rates below 30%. Existing treatments are often toxic and limited by drug resistance. Thiostrepton (TST), first isolated in the 1950s from Streptomyces azureus, has recently emerged as a promising anticancer agent due to its unique ability to inhibit tumor-related transcription factors and signaling pathways. Based on these challenges, it is necessary to explore thiostrepton’s therapeutic mechanisms in rhabdomyosarcoma through comprehensive experimental research.
A research team from the Children’s Hospital of Chongqing Medical University, China, reported (DOI: 10.1002/pdi3.70014) on June 29, 2025, in Pediatric Discovery that thiostrepton can significantly suppress rhabdomyosarcoma progression by targeting the PI3K–AKT signaling pathway. Using bioinformatics screening of GEO datasets and connectivity mapping, they identified thiostrepton as a top candidate for reversing tumor-associated gene expression. Laboratory experiments confirmed its ability to curb tumor growth both in cultured cells and animal models, providing compelling preclinical evidence for repurposing thiostrepton as an anti-rhabdomyosarcoma drug.
The study combined transcriptome analysis and pharmacological validation to uncover thiostrepton’s antitumor mechanisms. Researchers analyzed gene expression data from 84 tumor and 22 normal muscle samples, identifying 269 conserved differentially expressed genes and selecting thiostrepton via Connectivity Map scoring. In vitro, thiostrepton inhibited RMS cell proliferation in a dose- and time-dependent manner, with IC50 values of 4.986–9.764 μmol/L. It also blocked migration and invasion, triggered G0/G1 cell-cycle arrest, and induced apoptosis. In a xenograft mouse model, thiostrepton treatment (3.4 mg/mL for four weeks) substantially reduced tumor volume without damaging vital organs. RNA sequencing revealed that thiostrepton downregulated multiple oncogenic regulators, including AKT, JAK, and CDKs, while suppressing the PI3K–AKT pathway. Adding a PI3K activator partially reversed these effects, confirming the pathway’s central role. These findings position thiostrepton as a multi-mechanistic inhibitor that disrupts cancer cell survival, signaling, and proliferation.
“Our findings demonstrate that thiostrepton exerts broad-spectrum antitumor effects through a dual mechanism—directly impairing ribosomal protein synthesis and suppressing the PI3K–AKT signaling axis,” said corresponding author Professor Xiao-Mao Tian. “This approach not only halts cancer cell growth and invasion but also minimizes toxicity, which is crucial for pediatric therapy. Given its well-characterized safety profile as a veterinary antibiotic, thiostrepton could be rapidly advanced through preclinical testing and adapted for combination therapies in childhood rhabdomyosarcoma.”
The discovery of thiostrepton’s efficacy opens new avenues for drug repurposing in pediatric oncology. By targeting the PI3K–AKT signaling network—a pathway commonly associated with tumor resistance—thiostrepton offers a potential strategy to enhance the effectiveness of existing treatments while reducing side effects. Future research will focus on evaluating synergistic combinations with mTOR or immune checkpoint inhibitors to overcome therapeutic resistance. If validated in clinical studies, thiostrepton-based regimens could become an affordable and safe alternative for managing aggressive forms of rhabdomyosarcoma, improving survival prospects for young patients worldwide.
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References
DOI
10.1002/pdi3.70014
Original URL
https://doi.org/10.1002/pdi3.70014
Funding information
This work was supported by China Postdoctoral Science Foundation (2024M753886) and National Natural Science Foundation of China (82403383).
About Pediatric Discovery
Pediatric Discovery is a Gold Open Access publication and officially sponsored by The National Clinical Research Center for Child Health and Disorders of China, and Children's Hospital of Chongqing Medical University. The journal does not charge any submission fees. The Article Publication Charge (APC) is currently waived for accepted manuscripts. Pediatric Discovery is an open access and peer-reviewed international journal. The journal aims to advance the health and well-being of infants, children, and adolescents by disseminating cutting-edge discovery and knowledge in the field. It provides a platform for publishing and discussing the most important and state-of-the-art basic, translational and clinical discoveries affecting child and adolescent health and disorders in all aspects of pediatric medicine. Currently, this journal has been indexed by Pubmed Central and Directory of Open Access Journals (DOAJ).