Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1
Occurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibit...
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MDPI AG
2020-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/2/337 |
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| author | Chenyin Wang Alexandra Hamacher Patrick Petzsch Karl Köhrer Günter Niegisch Michèle J. Hoffmann Wolfgang A. Schulz Matthias U. Kassack |
| author_facet | Chenyin Wang Alexandra Hamacher Patrick Petzsch Karl Köhrer Günter Niegisch Michèle J. Hoffmann Wolfgang A. Schulz Matthias U. Kassack |
| author_sort | Chenyin Wang |
| collection | DOAJ |
| description | Occurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibitor decitabine (DAC) with the histone deacetylase inhibitor entinostat (ENT) in bladder cancer cells with different platinum sensitivities: J82, cisplatin-resistant J82CisR, and RT-112. Intermittent treatment of J82 cells with cisplatin resulted in the six-fold more cisplatin-resistant cell line J82CisR. Combinations of DAC and/or ENT plus cisplatin could not reverse chemoresistance. However, the combination of DAC and ENT acted cytotoxic in a highly synergistic manner as shown by Chou-Talalay analysis via induction of apoptosis and cell cycle arrest. Importantly, this effect was cancer cell-selective as no synergism was found for the combination in the non-cancerous urothelial cell line HBLAK. Expression analysis indicated that epigenetic treatment led to up-regulation of forkhead box class O1 (FoxO1) and further activated proapoptotic Bim and the cell cycle regulator p21 and reduced expression of survivin in J82CisR. In conclusion, the combination of DAC and ENT is highly synergistic and has a promising potential for therapy of bladder cancer, particularly in cases with platinum resistance. |
| first_indexed | 2024-03-12T10:36:34Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:36:34Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5ccfb83acf9e480cb99eeb4ead0aa85e2023-09-02T08:37:15ZengMDPI AGCancers2072-66942020-02-0112233710.3390/cancers12020337cancers12020337Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1Chenyin Wang0Alexandra Hamacher1Patrick Petzsch2Karl Köhrer3Günter Niegisch4Michèle J. Hoffmann5Wolfgang A. Schulz6Matthias U. Kassack7Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyBiological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyBiological and Medical Research Center (BMFZ), Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyDepartment of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, GermanyOccurrence of cisplatin-resistance in bladder cancer is frequent and results in disease progression. Thus, novel therapeutic approaches are a high medical need for patients suffering from chemotherapy failure. The purpose of this study was to test the combination of the DNA methyltransferase inhibitor decitabine (DAC) with the histone deacetylase inhibitor entinostat (ENT) in bladder cancer cells with different platinum sensitivities: J82, cisplatin-resistant J82CisR, and RT-112. Intermittent treatment of J82 cells with cisplatin resulted in the six-fold more cisplatin-resistant cell line J82CisR. Combinations of DAC and/or ENT plus cisplatin could not reverse chemoresistance. However, the combination of DAC and ENT acted cytotoxic in a highly synergistic manner as shown by Chou-Talalay analysis via induction of apoptosis and cell cycle arrest. Importantly, this effect was cancer cell-selective as no synergism was found for the combination in the non-cancerous urothelial cell line HBLAK. Expression analysis indicated that epigenetic treatment led to up-regulation of forkhead box class O1 (FoxO1) and further activated proapoptotic Bim and the cell cycle regulator p21 and reduced expression of survivin in J82CisR. In conclusion, the combination of DAC and ENT is highly synergistic and has a promising potential for therapy of bladder cancer, particularly in cases with platinum resistance.https://www.mdpi.com/2072-6694/12/2/337bladder cancercisplatindna methyltransferase inhibitordrug combination studyhistone deacetylase inhibitorforkhead box class o1 |
| spellingShingle | Chenyin Wang Alexandra Hamacher Patrick Petzsch Karl Köhrer Günter Niegisch Michèle J. Hoffmann Wolfgang A. Schulz Matthias U. Kassack Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 Cancers bladder cancer cisplatin dna methyltransferase inhibitor drug combination study histone deacetylase inhibitor forkhead box class o1 |
| title | Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 |
| title_full | Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 |
| title_fullStr | Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 |
| title_full_unstemmed | Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 |
| title_short | Combination of Decitabine and Entinostat Synergistically Inhibits Urothelial Bladder Cancer Cells via Activation of FoxO1 |
| title_sort | combination of decitabine and entinostat synergistically inhibits urothelial bladder cancer cells via activation of foxo1 |
| topic | bladder cancer cisplatin dna methyltransferase inhibitor drug combination study histone deacetylase inhibitor forkhead box class o1 |
| url | https://www.mdpi.com/2072-6694/12/2/337 |
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