Low-dose treatment with Epirubicin, a novel histone deacetylase 1 inhibitor, exerts anti-leukemic effects by inducing ferroptosis

Abstract

Aims: Leukemia is hematopoietic stem cell malignant tumor with poor outcomes. Histone deacetylase 1 (HDAC1) is highly expressed in leukemia and current HDAC1 inhibitors have clinical limitations in leukemia therapy. Therefore, novel HDAC1 inhibitor is imperative to being found and its mechanism needs to be further explored.

Materials and methods: Novel HDAC1 inhibitors were discovered through drug virtual screening. CCK-8, EdU and soft agar assay were used to assess the anti-leukemic effect of the candidate HDAC1 inhibitor. ROS, lipid peroxidation, intracellular Fe²⁺ and LIP assay were employed to verify cell ferroptosis. Additionally, a xenograft model was performed to explore the efficacy and safety of the candidate HDAC1 inhibitor in vivo.

Results: HDAC1 might be a promising therapeutic target for leukemia and Epirubicin (Epi) could be used as a potential HDAC1 inhibitor. Low-dose Epi exhibited good anti-leukemic effects by inhibiting cell proliferation, DNA synthesis and colony formation. Low-dose Epi could induce ferroptosis by triggering lipid peroxidation, which was better than that treated with current HDAC1 inhibitors Chidamide or Vorinostat, ROS generation and Fe²⁺ overload in leukemia cells. Mechanistically, low-dose Epi induced ferroptosis by targeting amino acid metabolism and iron metabolism. Similar results were found in a xenograft model in NOG mice with a good safety profile.

Conclusion: Our study demonstrated that Epi might be used as a HDAC1 inhibitor. Low-dose Epi could inhibit tumor progression by inducing cell ferroptosis in vitro and in vivo. Thus, Epi administration with lower concentration may be much more favorable and safer in the treatment with leukemia.

Keywords: Epirubicin; Ferroptosis; HDAC1; Leukemia.