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Open AccessArticle
Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer
by
Lukas M. Bollmann
Lukas M. Bollmann 1,
Friedrich Lange
Friedrich Lange 1,
Alexandra Hamacher
Alexandra Hamacher 1,
Lukas Biermann
Lukas Biermann 1,
Linda Schäker-Hübner
Linda Schäker-Hübner 2,
Finn K. Hansen
Finn K. Hansen 2 and
Matthias U. Kassack
Matthias U. Kassack 1,*
1
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Duesseldorf, 40225 Duesseldorf, Germany
2
Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
*
Author to whom correspondence should be addressed.
Submission received: 30 August 2024
/
Revised: 16 September 2024
/
Accepted: 30 September 2024
/
Published: 2 October 2024
Simple Summary
The treatment of bladder cancer is still a challenge. New treatment options are required for patients not responding to established chemotherapy (e.g., cisplatin) due to primary or acquired chemoresistance. Bladder cancer cells are known for disturbed epigenetics contributing to resistance. This study aimed to investigate the combination of cisplatin, the class I histone deacetylase inhibitor (HDACi) entinostat, and bromodomain inhibitors (BETis) in two urothelial grade 3 bladder carcinoma cell pairs J82, cisplatin-resistant J82 cisR, T24, and cisplatin-resistant T24 LTT. Our results indicate that treatment of bladder cancer cells with entinostat and a BETi prior to cisplatin can completely reverse cisplatin resistance. This is of particular interest since entinostat and OTX015 (one of the used BETi) are already in clinical trials in other cancers. Thus, this study encourages further preclinical and eventually clinical trials with epigenetic inhibitors in combination with cisplatin to re-establish cisplatin efficacy in bladder cancer.
Abstract
Background/Objectives. Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain inhibitors (BETis) on the potency of cisplatin in two pairs of sensitive and cisplatin-resistant bladder cancer cell lines. Cisplatin-resistant J82cisR and T24 LTT were 3.8- and 24-fold more resistant to cisplatin compared to the native cell lines J82 and T24. In addition, a hybrid compound (compound 20) comprising structural features of an HDACi and a BETi was investigated. Results. We found complete (J82cisR) or partial (T24 LTT) reversal of chemoresistance upon combination of entinostat, JQ1, and cisplatin. The same was found for the BETis JQ35 and OTX015, both in clinical trials, and for compound 20. The combinations were highly synergistic (Chou Talalay analysis) and increased caspase-mediated apoptosis accompanied by enhanced expression of p21, Bim, and FOXO1. Notably, the combinations were at least 4-fold less toxic in non-cancer cell lines HBLAK and HEK293. Conclusions. The triple combination of entinostat, a BETi, and cisplatin is highly synergistic, reverses cisplatin resistance, and may thus serve as a novel therapeutic approach for bladder cancer.
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MDPI and ACS Style
Bollmann, L.M.; Lange, F.; Hamacher, A.; Biermann, L.; Schäker-Hübner, L.; Hansen, F.K.; Kassack, M.U.
Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer. Cancers 2024, 16, 3374.
https://doi.org/10.3390/cancers16193374
AMA Style
Bollmann LM, Lange F, Hamacher A, Biermann L, Schäker-Hübner L, Hansen FK, Kassack MU.
Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer. Cancers. 2024; 16(19):3374.
https://doi.org/10.3390/cancers16193374
Chicago/Turabian Style
Bollmann, Lukas M., Friedrich Lange, Alexandra Hamacher, Lukas Biermann, Linda Schäker-Hübner, Finn K. Hansen, and Matthias U. Kassack.
2024. "Triple Combination of Entinostat, a Bromodomain Inhibitor, and Cisplatin Is a Promising Treatment Option for Bladder Cancer" Cancers 16, no. 19: 3374.
https://doi.org/10.3390/cancers16193374
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