Chidamide Reverses Fluzoparib Resistance in Triple-Negative Breast Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapy

Background:

• Drug resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a significant challenge in cancer treatment.
• Triple-negative breast cancer (TNBC) often develops resistance to PARPi, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the potential of chidamide to reverse fluzoparib resistance in TNBC.
• To elucidate the underlying mechanisms by which chidamide affects drug-resistant cells.

Main Methods:

• Construction of a fluzoparib-resistant TNBC cell line.
• In vitro and in vivo studies evaluating drug effects on cell proliferation, migration, invasion, cell cycle, and apoptosis.
• Bioinformatic analysis to identify key drug resistance genes and Western blotting to assess protein expression (PARP, RAD51, MRE11, cleaved Caspase9, P-CDK1).
• Xenograft mouse models were used for in vivo validation.

Main Results:

• Chidamide combined with fluzoparib significantly inhibited proliferation, migration, and invasiveness of resistant TNBC cells in vitro and in vivo.
• The combination therapy restored sensitivity to fluzoparib in resistant cells.
• Expression of key drug resistance genes RAD51 and MRE11 was significantly inhibited.
• Cell cycle arrest at the G2/M phase and induction of apoptosis were observed.

Conclusions:

• Chidamide demonstrates significant antineoplastic activity when combined with fluzoparib.
• This combination effectively reverses fluzoparib resistance in TNBC by downregulating RAD51 and MRE11 expression.
• The findings support the potential of chidamide and fluzoparib combination therapy for overcoming PARPi resistance in TNBC.