Drug screening approach combines epigenetic sensitization with immunochemotherapy in cancer

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http://hdl.handle.net/10138/309442

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Facciotto , C , Casado , J , Turunen , L , Leivonen , S-K , Tumiati , M , Rantanen , V , Kauppi , L , Lehtonen , R , Leppä , S , Wennerberg , K & Hautaniemi , S 2019 , ' Drug screening approach combines epigenetic sensitization with immunochemotherapy in cancer ' , Clinical epigenetics , vol. 11 , no. 1 , 192 . https://doi.org/10.1186/s13148-019-0781-3

Title: Drug screening approach combines epigenetic sensitization with immunochemotherapy in cancer
Author: Facciotto, Chiara; Casado, Julia; Turunen, Laura; Leivonen, Suvi-Katri; Tumiati, Manuela; Rantanen, Ville; Kauppi, Liisa; Lehtonen, Rainer; Leppä, Sirpa; Wennerberg, Krister; Hautaniemi, Sampsa
Contributor organization: Research Program in Systems Oncology
Faculty of Medicine
University of Helsinki
Sampsa Hautaniemi / Principal Investigator
Institute for Molecular Medicine Finland
Research Programs Unit
Genome-Scale Biology (GSB) Research Program
Department of Oncology
HUS Comprehensive Cancer Center
ATG - Applied Tumor Genomics
Medicum
Department of Biochemistry and Developmental Biology
Genome Stability Group
Krister Wennerberg / Principal Investigator
Date: 2019-12-11
Language: eng
Number of pages: 11
Belongs to series: Clinical epigenetics
ISSN: 1868-7083
DOI: https://doi.org/10.1186/s13148-019-0781-3
URI: http://hdl.handle.net/10138/309442
Abstract: Background The epigenome plays a key role in cancer heterogeneity and drug resistance. Hence, a number of epigenetic inhibitors have been developed and tested in cancers. The major focus of most studies so far has been on the cytotoxic effect of these compounds, and only few have investigated the ability to revert the resistant phenotype in cancer cells. Hence, there is a need for a systematic methodology to unravel the mechanisms behind epigenetic sensitization. Results We have developed a high-throughput protocol to screen non-simultaneous drug combinations, and used it to investigate the reprogramming potential of epigenetic inhibitors. We demonstrated the effectiveness of our protocol by screening 60 epigenetic compounds on diffuse large B-cell lymphoma (DLBCL) cells. We identified several histone deacetylase (HDAC) and histone methyltransferase (HMT) inhibitors that acted synergistically with doxorubicin and rituximab. These two classes of epigenetic inhibitors achieved sensitization by disrupting DNA repair, cell cycle, and apoptotic signaling. The data used to perform these analyses are easily browsable through our Results Explorer. Additionally, we showed that these inhibitors achieve sensitization at lower doses than those required to induce cytotoxicity. Conclusions Our drug screening approach provides a systematic framework to test non-simultaneous drug combinations. This methodology identified HDAC and HMT inhibitors as successful sensitizing compounds in treatment-resistant DLBCL. Further investigation into the mechanisms behind successful epigenetic sensitization highlighted DNA repair, cell cycle, and apoptosis as the most dysregulated pathways. Altogether, our method adds supporting evidence in the use of epigenetic inhibitors as sensitizing agents in clinical settings.
Subject: 1184 Genetics, developmental biology, physiology
Epigenetic
Epigenetic reprogramming
Epigenetic inhibitors
High-throughput drug screening
3122 Cancers
Diffuse large B-cell lymphoma
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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