The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.
Keywords: DLBCL; DNA damage; JNK; Mitochondrial dysfunction; ROS.
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