Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway
Abstract Background The anti-osteosarcoma effects of hydrocortisone and thiram, an inhibitor of type 2 11ß-hydroxysteroid dehydrogenase (11HSD2), have not been reported. The purpose of this study was to investigate the effects of hydrocortisone alone or the combination of hydrocortisone with thiram...
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BMC
2023-03-01
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| Series: | BMC Pharmacology and Toxicology |
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| Online Access: | https://doi.org/10.1186/s40360-023-00655-0 |
| _version_ | 1797853573463146496 |
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| author | You Zhang Nanjing Li He Li Maojia Chen Wei Jiang Wenhao Guo |
| author_facet | You Zhang Nanjing Li He Li Maojia Chen Wei Jiang Wenhao Guo |
| author_sort | You Zhang |
| collection | DOAJ |
| description | Abstract Background The anti-osteosarcoma effects of hydrocortisone and thiram, an inhibitor of type 2 11ß-hydroxysteroid dehydrogenase (11HSD2), have not been reported. The purpose of this study was to investigate the effects of hydrocortisone alone or the combination of hydrocortisone with thiram on osteosarcoma and the molecular mechanism, and determine whether they can be as new therapeutic agents for osteosarcoma. Methods Normal bone cells and osteosarcoma cells were treated with hydrocortisone or thiram alone or in combination. The cell proliferation, migration, cell cycle and apoptosis were detected by using CCK8 assay, wound healing assay, and flow cytometry, respectively. An osteosarcoma mouse model was established. The effect of drugs on osteosarcoma in vivo was assessed by measuring tumor volume. Transcriptome sequencing, bioinformatics analysis, RT–qPCR, Western blotting (WB), enzymelinked immunosorbent assay (ELISA) and siRNA transfection were performed to determine the molecular mechanisms. Results Hydrocortisone inhibited the proliferation and migration, and induced apoptosis and cell cycle arrest of osteosarcoma cells in vitro. Hydrocortisone also reduced the volume of osteosarcoma in mice in vivo. Mechanistically, hydrocortisone decreased the levels of Wnt/β-catenin pathway-associated proteins, and induced the expression of glucocorticoid receptor α (GCR), CCAAT enhancer-binding protein β (C/EBP-beta) and 11HSD2, resulting in a hydrocortisone resistance loop. Thiram inhibited the activity of the 11HSD2 enzyme, the combination of thiram and hydrocortisone further enhanced the inhibition of osteosarcoma through Wnt/β-catenin pathway. Conclusions Hydrocortisone inhibits osteosarcoma through the Wnt/β-catenin pathway. Thiram inhibits 11HSD2 enzyme activity, reducing hydrocortisone inactivation and promoting the effect of hydrocortisone through the same pathway. |
| first_indexed | 2024-04-09T19:51:44Z |
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| id | doaj.art-43bc5792f8924683b4e546994a7a3f2a |
| institution | Directory Open Access Journal |
| issn | 2050-6511 |
| language | English |
| last_indexed | 2024-04-09T19:51:44Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pharmacology and Toxicology |
| spelling | doaj.art-43bc5792f8924683b4e546994a7a3f2a2023-04-03T05:40:39ZengBMCBMC Pharmacology and Toxicology2050-65112023-03-0124111510.1186/s40360-023-00655-0Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathwayYou Zhang0Nanjing Li1He Li2Maojia Chen3Wei Jiang4Wenhao Guo5Clinical Translational Innovation Center/Molecular Medicine Research Center, West China Hospital, Sichuan UnivicityDivision of of Radiotherapy, Cancer Center,West China Hospital, Sichuan UniversityWest China School of Basic Medical Sciences & Forensic Medicine, Sichuan UniversityAnimal Experiment Center, West China Hospital, Sichuan UniversityClinical Translational Innovation Center/Molecular Medicine Research Center, West China Hospital, Sichuan UnivicityDepartment of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, Medical School, West China Hospital, Sichuan UniversityAbstract Background The anti-osteosarcoma effects of hydrocortisone and thiram, an inhibitor of type 2 11ß-hydroxysteroid dehydrogenase (11HSD2), have not been reported. The purpose of this study was to investigate the effects of hydrocortisone alone or the combination of hydrocortisone with thiram on osteosarcoma and the molecular mechanism, and determine whether they can be as new therapeutic agents for osteosarcoma. Methods Normal bone cells and osteosarcoma cells were treated with hydrocortisone or thiram alone or in combination. The cell proliferation, migration, cell cycle and apoptosis were detected by using CCK8 assay, wound healing assay, and flow cytometry, respectively. An osteosarcoma mouse model was established. The effect of drugs on osteosarcoma in vivo was assessed by measuring tumor volume. Transcriptome sequencing, bioinformatics analysis, RT–qPCR, Western blotting (WB), enzymelinked immunosorbent assay (ELISA) and siRNA transfection were performed to determine the molecular mechanisms. Results Hydrocortisone inhibited the proliferation and migration, and induced apoptosis and cell cycle arrest of osteosarcoma cells in vitro. Hydrocortisone also reduced the volume of osteosarcoma in mice in vivo. Mechanistically, hydrocortisone decreased the levels of Wnt/β-catenin pathway-associated proteins, and induced the expression of glucocorticoid receptor α (GCR), CCAAT enhancer-binding protein β (C/EBP-beta) and 11HSD2, resulting in a hydrocortisone resistance loop. Thiram inhibited the activity of the 11HSD2 enzyme, the combination of thiram and hydrocortisone further enhanced the inhibition of osteosarcoma through Wnt/β-catenin pathway. Conclusions Hydrocortisone inhibits osteosarcoma through the Wnt/β-catenin pathway. Thiram inhibits 11HSD2 enzyme activity, reducing hydrocortisone inactivation and promoting the effect of hydrocortisone through the same pathway.https://doi.org/10.1186/s40360-023-00655-011ß-hydroxysteroid dehydrogenase type 2HydrocortisoneThiramOsteosarcomaWnt/β-catenin pathway |
| spellingShingle | You Zhang Nanjing Li He Li Maojia Chen Wei Jiang Wenhao Guo Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway BMC Pharmacology and Toxicology 11ß-hydroxysteroid dehydrogenase type 2 Hydrocortisone Thiram Osteosarcoma Wnt/β-catenin pathway |
| title | Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway |
| title_full | Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway |
| title_fullStr | Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway |
| title_full_unstemmed | Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway |
| title_short | Thiram, an inhibitor of 11ß-hydroxysteroid dehydrogenase type 2, enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through Wnt/β-catenin pathway |
| title_sort | thiram an inhibitor of 11ss hydroxysteroid dehydrogenase type 2 enhances the inhibitory effects of hydrocortisone in the treatment of osteosarcoma through wnt β catenin pathway |
| topic | 11ß-hydroxysteroid dehydrogenase type 2 Hydrocortisone Thiram Osteosarcoma Wnt/β-catenin pathway |
| url | https://doi.org/10.1186/s40360-023-00655-0 |
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