2. Academic Validation
  3. Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

Decitabine potentiates efficacy of doxorubicin in a preclinical trastuzumab-resistant HER2-positive breast cancer models

  • Biomed Pharmacother. 2022 Mar;147:112662. doi: 10.1016/j.biopha.2022.112662.
Verona Buocikova 1,  Eleonora Marta Longhin 2,  Eleftherios Pilalis 3,  Chara Mastrokalou 4,  Svetlana Miklikova 1,  Marina Cihova 1,  Alexandra Poturnayova 5,  Katarina Mackova 5,  Andrea Babelova 1,  Lenka Trnkova 1,  Naouale El Yamani 2,  Congying Zheng 6,  Ivan Rios-Mondragon 7,  Martina Labudova 8,  Lucia Csaderova 8,  Kristina Mikus Kuracinova 9,  Peter Makovicky 1,  Lucia Kucerova 1,  Miroslava Matuskova 1,  Mihaela Roxana Cimpan 7,  Maria Dusinska 2,  Pavel Babal 9,  Aristotelis Chatziioannou 3,  Alena Gabelova 1,  Elise Rundén-Pran 2,  Bozena Smolkova 10
Affiliations

Affiliations

  • 1 Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
  • 2 Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway.
  • 3 e-NIOS Applications P.C., AlexandrouPantou 25, Kallithea 17671, Athens, Greece; Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Greece.
  • 4 Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Greece.
  • 5 Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
  • 6 Norgenotech AS, Ullernchassern, 64/66 Oslo, Norway.
  • 7 Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway.
  • 8 Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia.
  • 9 Department of Pathology, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
  • 10 Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia. Electronic address: bozena.smolkova@savba.sk.
PMID: 35091237 DOI: 10.1016/j.biopha.2022.112662
Abstract

Acquired drug resistance and metastasis in breast Cancer (BC) are coupled with epigenetic deregulation of gene expression. Epigenetic drugs, aiming to reverse these aberrant transcriptional patterns and sensitize Cancer cells to other therapies, provide a new treatment strategy for drug-resistant tumors. Here we investigated the ability of DNA Methyltransferase (DNMT) inhibitor decitabine (DAC) to increase the sensitivity of BC cells to anthracycline Antibiotic doxorubicin (DOX). Three cell lines representing different molecular BC subtypes, JIMT-1, MDA-MB-231 and T-47D, were used to evaluate the synergy of sequential DAC + DOX treatment in vitro. The cytotoxicity, genotoxicity, Apoptosis, and migration capacity were tested in 2D and 3D cultures. Moreover, genome-wide DNA methylation and transcriptomic analyses were employed to understand the differences underlying DAC responsiveness. The ability of DAC to sensitize trastuzumab-resistant HER2-positive JIMT-1 cells to DOX was examined in vivo in an orthotopic xenograft mouse model. DAC and DOX synergistic effect was identified in all tested cell lines, with JIMT-1 cells being most sensitive to DAC. Based on the whole-genome data, we assume that the aggressive behavior of JIMT-1 cells can be related to the enrichment of epithelial-to-mesenchymal transition and stemness-associated pathways in this cell line. The four-week DAC + DOX sequential administration significantly reduced the tumor growth, DNMT1 expression, and global DNA methylation in xenograft tissues. The efficacy of combination therapy was comparable to effect of pegylated liposomal DOX, used exclusively for the treatment of metastatic BC. This work demonstrates the potential of epigenetic drugs to modulate Cancer cells' sensitivity to other forms of Anticancer therapy.

Keywords

Breast cancer; Combination therapy; DNA methylation; Decitabine; Doxorubicin; Epigenetic drugs.

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