Molecular, biological characterization and drug sensitivity of chidamide-resistant MCF7 cells

Chidamide (CHI) is a subtype-selective histone deacetylase inhibitor (HDACI) developed in China and approved as a second-line treatment combined with the aromatase inhibitor for hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) advanced breast cancer. However, drug resistance is commonly occurred after a long period of medication. This study aimed to investigate the characterization of induced resistance to CHI and explore the potential cross-resistance to chemotherapeutic agents.

CHI with gradually increasing concentrations was added to breast cancer MCF7 cells to establish a CHI-resistant MCF7 (MCF7-CHI-R) cell line. Cell counting kit-8 (CCK-8) assays were performed to detect half-maximal inhibitory concentration (IC₅₀) of CHI. Colony formation was used to determine the proliferation inhibition rate. Western blot analysis was conducted to detect expressions of protein related with cell cycle, apoptosis, ferroptosis, and histone deacetylase (HDAC). Flow cytometry was used to analyze apoptosis and cell cycle.

The IC₅₀ value of CHI of MCF7-CHI-R cells was increased in comparison with MCF7 cells. And CHI led to cell cycle arrest and ferroptosis, which were not exhibited in MCF7-CHI-R cells. Moreover, HDAC activity decreased in MCF7-CHI-R cells in comparison with MCF7 cells, and HDAC1 and HDAC10 might be involved in the resistance to CHI. In addition, MCF7-CHI-R cells were resistant to gemcitabine (GEM), doxorubicin (ADM), docetaxel (DXT), albumin-bound paclitaxel (nab-PTX) and paclitaxel (PTX).

The MCF7-CHI-R was established and the anti-ferroptosis pathway activation was involved in the resistance of MCF-CHI-R cells. Also, MCF7-CHI-R cells were resistant to GEM, ADM, DXT, nab-PTX and PTX.