Enhanced efficacy of combined fluzoparib and chidamide targeting in natural killer/T-cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Natural killer/T-cell lymphoma (NKTCL) treatment is challenging, necessitating novel therapeutic strategies.
• Poly ADP-ribose polymerase inhibitors (PARPi) show efficacy in various cancers, but their use in NKTCL is unexplored.
• Histone deacetylase inhibitors (HDACis) are also investigated for cancer therapy.

Purpose of the Study:

• To investigate the synergistic cytotoxic effects of combining a novel PARP inhibitor, fluzoparib, with a classical HDAC inhibitor, chidamide, against NKTCL.
• To elucidate the underlying mechanisms of action, including DNA damage, apoptosis, and reactive oxygen species (ROS) generation.

Main Methods:

• In vitro cytotoxicity assays using NKTCL cell lines treated with fluzoparib and/or chidamide.
• In vivo efficacy studies in YT-luciferin xenograft mouse models.
• Analysis of DNA damage repair pathway proteins (p-ATM, p-BRCA1, p-ATR, Rad51) and intracellular ROS levels.

Main Results:

• Both fluzoparib and chidamide inhibited NKTCL cell proliferation in a dose-dependent manner.
• The combination treatment synergistically induced DNA double-strand breaks and apoptosis by inhibiting DNA repair pathways.
• Combined therapy increased intracellular ROS, enhancing apoptosis, an effect partially reversed by ROS scavengers.
• Synergistic antitumor effects were confirmed in vivo in xenograft models.

Conclusions:

• The combination of fluzoparib and chidamide demonstrates synergistic antitumor activity against NKTCL both in vitro and in vivo.
• This combination effectively targets DNA damage repair and promotes apoptosis, making it a promising therapeutic strategy for NKTCL.
• Further clinical investigation of this combined regimen for NKTCL is warranted.