HDACi Promotes the Occurrence of Ferroptosis in CTCL

Cutaneous T-cell lymphoma (CTCL) is a type of extranodal non-Hodgkin's lymphoma (NHL), a disease caused by clonal proliferation of T-lymphocytes originating in the skin. CHOP is the classic first-line treatment regimen for PTCL, working best for ALK-positive ALCL, while chemotherapy regimens are not very friendly for CTCL and other subtypes of PTCL. Currently, second-line treatment regimens have shown encouraging results with HDAC inhibitors in PTCL, and the anti-tumor mechanisms of HDAC inhibitors are being explored, including induction of apoptosis, cell cycle arrest inhibition of tumor angiogenesis, and so on.

Ferroptosis is a new mode of cell death, which was mainly manifested by mitochondrial membrane lipid peroxidation, ferritin phagocytosis, the release of ferrous ions. And ferrous ions further leads to cellular lipid peroxidation, resulting in cell death. Our study shows that HDACi can significantly enhance ferroptosis inducer-mediated ferroptosis. WB and qPCR showed that ferroptosis-related molecules were significantly downregulated. In the case of HDACi combined with ferroptosis inducer, HDACi significantly enhanced the intensity of ferroptosis, and mitochondrial shrinkage and increased membrane density could be observed under electron microscopy. Intracellular iron content was detected by PGSK probe and detected by co Focused microscopy revealed that the fluorescence signal was significantly attenuated in the combination group. Reactive oxygen species assay indicated a significant increase in intracellular reactive oxygen species level, where we found the presence of ferroptosis in PTCL for the first time. In addition, we found that HDACi combined with ferroptosis inducer could enhance the apoptosis level of lymphoma cells, and the combination group significantly downregulated BCL-2, Caspase3,and significantly upregulated p-H2AX expression compared with the single drug.In terms of cycle arrest, CyclinD1 was significantly down-regulated in the combination group, and flow cytometry results were consistent with the above, while CCK8 and Edu showed significant down-regulation of cell viability and proliferation. SD rat transplantation tumor models showed a significant reduction in tumor volume in the combination group compared to the single agent and control groups, suggesting that HDACI combined with ferroptosis inducer is a promising therapeutic strategy.

No relevant conflicts of interest to declare.