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

• DOI: 10.1016/j.biopha.2022.112662
• Publication Date: 2022-01-25T05:12:16Z
• Authors: Verona Buocikova; Eleonora Marta Lo...; Eleftherios Pilalis; Chara Mastrokalou; Svetlana Miklikova; Marina Cihova; Alexandra Poturna...; Katarina Mackova; Andrea Babelova; Lenka Trnkova; Naouale El Yamani; Congying Zheng; Ivan Rios-Mondragon; Martina Labudova; Lucia Csaderova; Kristina Mikus Ku...; Peter Makovicky; Lucia Kucerova; Miroslava Matuskova; Mihaela Roxana Ci...; Maria Dusinska; Pavel Babal; Aristotelis Chatz...; Alena Gabelova; Elise Rundén-Pran; Bozena Smolkova
• Keywords: Decitabine; DNMT1; Azacitidine; DNA methyltransferase

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