thiostrepton (RSO-021)

Moreover, c-FLIP overexpression significantly increased the expression and phosphorylation of SMAD2/3 proteins and vice versa. In conclusion, our study reveals c-FLIP/SMAD2/3 signaling pathway as a novel mechanism of antitumor activity of thiostrepton.

Treatment with thiostrepton, a FOXM1 inhibitor, not only suppressed ASF1B expression, but also inhibited GC progression...The crucial role of ASF1B-regulated PRDX3 in GC cell proliferation and oxidative stress balance was also elucidated. In summary, our study suggests that the FOXM1-ASF1B-PRDX3 axis is a potential therapeutic target for treating GC.

Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a dose-dependent manner. These findings suggest that FOXM1 is a promising therapeutic target for patients with EMPD.

The combined treatment of a PLK1 inhibitor (volasertib) and a FoxM1 inhibitor (thiostrepton) demonstrated a synergistic effect in reducing PTC cell growth in vitro and delaying tumor growth in vivo. This study highlights the important role of PLK1 in PTC tumorigenesis and prognosis. It also highlights the synergistic therapeutic potential of dual-targeting PLK1 and FoxM1 in PTC, unveiling a potential innovative therapeutic strategy for managing aggressive forms of PTC.

P1/2, N=186, Recruiting, RS Oncology LLC | N=72 --> 186

Not available.

Our model was validated using a known NRF2 activator, after which we screened 1200 FDA-approved drugs, unearthing six compounds (Disulfiram, Thiostrepton, Auranofin, Thimerosal, Halofantrine, and Vorinostat) that enhanced NRF2 activity and antioxidant response. These compounds demonstrated protective effects against oxidative stress induced by hydrogen peroxide and lipid droplets accumulation in vitro with hepatoma HUH-7 cells. Our study underscores the utility of CRISPR/Cas9 tagging with Nanoluc luciferase in identifying potential NRF2 activators, paving the way for potential NAFLD therapeutics.

Our results suggest that sarcomatoid transformation exhibits adaption to hypoxia via a TGF-β/TEAD/EMT axis which is reversible by PRX3 inhibition.

Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis. Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.

Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the DDX5 (p68)/β-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by DDX5 (p68) and β-catenin in colorectal cancer.

FOXM1 inhibition by thiostrepton showed that co-treatment caused FOXM1-mediated cell death. Flow cytometry showed that the accumulation of cells in the G2/M and S phases might be linked to cellular Dox uptake, p21 upregulation, and cyclin D1 downregulation. Taken together, our study shows that the anti-tumor effect of morin/Dox co-treatment is due to the suppression of FOXM1 and attenuation of EGFR/STAT3 signaling pathways in MDA-MB-231 TNBC cells, which suggests that morin offers a means of improving therapeutic efficacy in TNBC patients.

The first patient commenced treatment in March 2022. Clinicaltrial.gov identifier: NCT05278975.

Anticancer activities of thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, quinine sulfate showed significant anti-proliferative properties in Hela cells, pancreatic, prostate, breast, lungs, melanoma, B-lymphocytes, T-cells (40% to 95%). Pure plasma mRNAs and miRNAs of pre-dose vs. post-dose of NS-3 treated samples were analyzed by Next Generation Sequencing (NGS). Venn diagrams have established genetic regulatory network images and canonical signaling pathways for mRNA, miRNA, and paired mRNA-miRNA.

We identified that conventional drugs such as cytarabine and venetoclax had significant cytotoxic effects on AML blasts, albeit with heterogeneous efficacies dependent on AML subtype, while M2 macrophages remained largely unaffected. In conclusion, our screening setup allows for the identification of compounds that can target both leukemic blasts as well as their tumor supportive microenvironment, and thiostrepton, KPT-9274 and metformin emerged as potentially promising candidates. We hope that (combinatorial) targeted drug treatments that also take the tumor microenvironment into account can help to improve AML treatment and prevent relapse.

This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.

Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation...In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3 T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.

Both in vitro and in vivo studies illustrated that THIO strongly promoted the drug-resistant gastric cancer cells to chemotherapies, proved by the considerably decreased cell proliferation and epithelial-mesenchymal transition (EMT) process. Together, these findings revealed that FOXM1 was a promising therapeutic target for gastric cancer treatment, and THIO exerted potential as an therapeutic agent for the disease.

Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.

Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.

Taken together, these results reveal a new mechanism by which c-FLIP regulates FoxM1 and the function of this interaction in the development of thiostrepton and osimertinib resistance. This study provides experimental evidence for the potential therapeutic benefit of targeting the c-FLIP-FoxM1 axis for lung cancer treatment.

Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.