Thiostrepton

Thiostrepton | FOXM1 inhibitor | YAP/TEAD/FOXM1 complex | Antitumor peptide | Science-Peptide

【Properties】White or off-white powder
【Purity】≥95%
【Package】5mg, 10mg
【Storage】2-8℃, Storage -20℃, sealed storage
【More Information] Peptide price, sequence information, chemical structure, molecular weight, scientific research literature, please email inquiry

Thiostrepton (TST), a thiazole cyclic peptide antibiotic from Streptomyces, has recently been identified as a specific inhibitor of the transcription factor FOXM1, which is a key oncogene transcription factor that regulates cell cycle progression, genome stability, and DNA repair, and is highly expressed in various tumors, and is closely related to tumorigenesis, progression, and drug resistance. This compound directly binds to FOXM1 protein, reduces its transcriptional activity, and down-regulates FOXM1 expression at the transcriptional and promoter levels; FOXM1 binds to the YAP/TEAD transcriptional complex, and together they play a transcriptional role in the regulatory regions of cell cycle-controlled genes, affecting cell proliferation. Based on the above mechanism, this antibiotic shows a wide range of applications in anti-tumor research.

Study of the mechanism of direct targeting of FOXM1
A study published in Nature Chemistry in 2011 demonstrated that Thiostrepton directly interacts with the FOXM1 protein in human breast cancer cells MCF-7. Biophysical analysis showed that it binds specifically to FOXM1 and inhibits the binding of FOXM1 to genomic target sites in cellular assays. This study is the first to elucidate the mode of action of this compound in targeting FOXM1 at the molecular level. Another study revealed that it down-regulated FOXM1 protein levels through redox-dependent and proteasome-dependent mechanisms, and the down-regulation was prevented by the antioxidant NAC and the proteasome inhibitor MG132.

YAP/TEAD/FOXM1 transcription complex studies
A 2017 study published in Gastroenterology found that in hepatocellular carcinoma cells, YAP/TEAD4 drives chromosomal instability gene expression profiles through induction and binding of FOXM1. Inhibition of FOXM1 with Thiostrepton or blockade of the YAP-TEAD4 interaction with Verteporfin reduced the chromosomal instability gene expression pattern. Injection of this agent in YAPS127A transgenic mice reduced liver overgrowth and signs of chromosomal instability, suggesting that targeting this complex may be a new strategy for hepatocellular carcinoma treatment.

Induction of cell cycle arrest and apoptosis studies
Thiostrepton selectively induced breast cancer cell cycle arrest in G₁ and S phases and led to cell death through down-regulation of FOXM1, while it had no effect on FOXM1 expression and proliferation in non-transformed MCF-10A mammary epithelial cells, showing selective toxicity to cancer cells. In laryngeal squamous cell carcinoma (LSCC), this compound inhibited cell viability in a dose- and time-dependent manner, induced S-phase cell cycle arrest and DNA synthesis inhibition, and induced apoptosis via the mitochondria-dependent caspase-intrinsic pathway and the Fas-dependent extrinsic pathway. In a nude mouse LSCC xenograft model, treatment with this antibiotic significantly inhibited tumorigenesis, proliferation and induced apoptosis.

Triple negative breast cancer (TNBC) study
In MDA-MB-231 TNBC cells, Thiostrepton induced mitotic spindle abnormalities, mitotic arrest, and apoptotic cell death, significantly enhanced paclitaxel cytotoxicity, and remained effective in paclitaxel-resistant cell lines. A 2022 study showed that this agent alone significantly inhibited tumor growth, lung metastasis, and the number of tumor foci in a 4T1 TNBC syngeneic transplant model, and inhibited FoxM1 expression.

Combination drug use and drug resistance reversal studies
Thiostrepton, in combination with the PARP inhibitor Olaparib, produced a greater reduction in cell viability in breast cancer cells by increasing DNA double-strand breaks than the single agent. In chemotherapy-resistant ovarian cancer, this compound down-regulated FOXM1 and its downstream targets CCNB1 and CDC25B, and showed synergistic effects in combination with paclitaxel and cisplatin. In addition, it down-regulated the expression of osteosarcoma stem cell markers and enhanced the drug sensitivity to cisplatin.

Research on other tumor types
Thiostrepton promotes anti-tumor immune response in intrahepatic cholangiocarcinoma through FOXM1-mediated reprogramming of tumor-associated macrophages polarized toward M1 phenotype. In gastric cancer, inhibition of FOXM1-induced oxidative stress, autophagy and apoptosis significantly slowed cell proliferation, migration, invasion and angiogenesis. In a subcutaneous xenograft model of pancreatic cancer, 17 mg/kg treatment with this antibiotic significantly inhibited tumor growth.