BDA-366 inhibits extra-nodal natural killer/T-cell lymphoma by inducing mitochondria damage through NF-κB pathway

Advanced extra-nodal natural killer/T-cell lymphoma (ENKTL) patients tend to be resistant to multiple chemotherapy drugs. Studies have shown that high expression of B-cell lymphoma 2 (BCL-2) is associated with poor prognosis and drug resistance of ENKTL, hence it is a potential therapy target. The BCL-2 homology (BH) domain 4 is essential for the anti-apoptotic function of BCL-2. Compared with BH3 domain, BH4 domain participates in more biological processes than just anti-apoptosis. Therefore, we tested the anti-tumor effect of BDA-366, a promising BCL-2 BH4 domain inhibitor, in treating ENKTL cells. The results showed that ENKTL cells were more sensitive to BDA-366 than other small-molecule inhibitors, such as ABT-199, S63845 and Chidamide. BDA-366 strongly induced apoptosis of ENKTL cells in vitro and significantly inhibited tumor growth in vivo with no obvious cytotoxicity to normal hematopoietic cells. Moreover, treatment with BDA-366 elevated reactive oxygen species (ROS) level and induced mitochondria damage in ENKTL cells, as evidenced by decreased mitochondrial membrane potential (MMP) and increased Ca²⁺ release. Gene Ontology (GO) enrichment analysis showed significant change of nuclear factor-kappaB (NF-κB) pathway in ENKTL cells treated with BDA-366, and by western blot, the expression of NF-κB p65 and mitochondrial function-related protein peroxisome proliferator-activated receptor γ coactivator-1β (PGC1β) were shown to be downregulated. In conclusion, as a BCL-2 BH4 domain antagonist, BDA-366 exhibited potent anti-tumor effect on ENKTL cells both in vitro and in vivo by triggering mitochondria-mediated apoptosis through suppressing NF-κB signaling pathway. Therefore, BDA-366 is a promising drug to treat ENKTL and overcome chemotherapy resistance.