Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy

Abstract

Abstract. Medulloblastoma (MB) is the most common malignant brain tumor in children and is highly invasive and metastatic. Despite recent advances, most MB patients suffer significant therapy-related morbidity, and the survival rate for patients with metastatic MB remains unsatisfactory. Altered expression of FOXM1 has been detected in many types of cancers, and the inhibition of FOXM1 has been studied as a cancer therapy. In the present study, we evaluated the impact of the inhibition of FOXM1 by thiostrepton in Daoy MB cells. Cells were treated with different concentrations of thiostrepton alone or in combination with cisplatin. Cell viability was measured with CCK-8 assays, and cell cycle distribution and apoptosis were assessed by flow cytometric analysis. Changes in protein expression were examined by western blotting. RNAi experiments were performed using siRNA oligonucleotides. The invasion and migration studies were performed using 8-µm Transwell plates. Inhibition of FOXM1 by thiostrepton significantly decreased MB cell proliferation. Cell arrest at the G2/M phase and apoptosis were significantly increased in MB cell lines that were treated with thiostrepton or transfected with siRNA. Thiostrepton decreased the IC 50 value of cisplatin for MB treatment by enhancing cisplatininduced apoptosis. Thiostrepton also decreased cell invasion and migration, which are crucial steps for tumor progression. Our data suggest that targeting FOXM1 with small-molecule inhibitors results in potent antitumor activity and chemosensitizing effects in human medulloblastoma cells.

A FOXM1 Dependent Mesenchymal-Epithelial Transition in Retinal Pigment Epithelium Cells

“…Thiostrepton treatment resulted in a reduction in FOXM1 expression which correlated with a decrease in EdU incorporation with comparable IC 50 values (1.1 μM and 0.6 μM respectively) ( Fig 3E ). This indicates that the inhibitor has a similar efficacy for both readouts and is consistent with its IC 50 estimated in previous studies [ 34 , 35 ]. In addition, we performed an in-vitro wound closure assay as an alternative way to measure proliferation and migration potential of epithelial cells.…”

Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia

“…The present study investigated the antileukemic effects of thiostrepton on Jurkat cell proliferation. Thiostrepton significantly inhibited the proliferation of Jurkat cells, and the IC 50 value of thiostrepton in the Jurkat cells following 48 h treatment was 1.52 µmol/l, suggesting the sensitivity of the Jurkat cells to thiostrepton was comparable to that of other types of cancer cell (28,29). Furthermore, the results of the present study indicated that thiostrepton induced G2/M cell cycle phase arrest and increased apoptosis in the Jurkat cells.…”

“…Previous studies have suggested that silencing FoxM1 enhances sensitivity to chemotherapeutic agents in various types of cancer cells (14,29), therefore, the present study investigated whether the thiostrepton-mediated inhibition of FoxM1 sensitized the Jurkat cells to the effects of chemotherapy. the IC 50 value of doxorubicin in the Jurkat cells decreased between 0.295 and 0.198 µmol/l when thiostrepton (1 µmol/l) was used in combination.…”

Curcumin suppresses cell proliferation through inhibition of the Wnt/β-catenin signaling pathway in medulloblastoma

“…It is one of the leading causes of morbidity and mortality in pediatric cancer (1). Recently, the survival rates have shown improvement; yet, patients undergoing current treatment regimes suffer from serious therapy-related side-effects, such as loss of hearing and cognitive impairment (2). Due to its high mortality rate and the post-treatment disabilities of current therapies, there is an urgent need for the development of nontoxic and efficient agents for MB.…”