What question did this study set out to answer?

This research aims to assess the effectiveness and underlying mechanisms of Z2-A-Z2 in targeting NF-κB signaling in DLBCL.

May 20, 2026Open Access

Superior anti-DLBCL efficacy of novel organic arsenical Z2-A-Z2 through ROS-mediated apoptosis and critical NF-κB/IκBα signaling pathway inhibition

WWWenjiao WeiHubei University of Medicine YMYanni MaArmy Medical University YLYujiao LiuWuhan Polytechnic University

Key Points

This research aims to assess the effectiveness and underlying mechanisms of Z2-A-Z2 in targeting NF-κB signaling in DLBCL.
Synthesized Z2-A-Z2, verified using NMR and mass spectrometry.
Evaluated anti-proliferative activity in DLBCL cell lines and normal PBMCs using CCK-8 assays.
Utilized flow cytometry and Western blot analyses to study apoptosis and NF-κB pathway proteins.
Z2-A-Z2 showed an average IC₅₀ of approximately 1.1 µM, outperforming arsenic trioxide (3- to 6-fold).
Induced significant apoptosis and G2/M cell cycle arrest through ROS-mediated oxidative stress and NF-κB inhibition.
In vivo studies demonstrated substantial tumor growth suppression in xenograft models with elevated apoptosis and reduced NF-κB activity.

Abstract

Abstract Objective Diffuse large B-cell lymphoma (DLBCL) often resists therapy due to aberrant activation of NF-κB signaling pathway. We synthesized and evaluated Z2-A-Z2, a novel organic arsenical, hypothesized to target this survival pathway, aiming to assess its efficacy and mechanism against DLBCL. Materials and methods The novel compound Z2-A-Z2 was synthesized and verified by 1 H CMR, 13 C CMR, and high-resolution mass spectrometry. Its anti-proliferative activity was assessed in GCB- and ABC-subtype DLBCL cell lines and normal peripheral blood mononuclear cells (PBMCs) using CCK-8 assays. Mechanisms were elucidated through flow cytometry (apoptosis, ROS, ΔΨm), Western blot (apoptotic and NF-κB pathway proteins), and enzyme activity assays. The causal role of ROS was confirmed by N-Acetylcysteine rescue (NAC) experiments, and the criticality of NF-κB inhibition was validated using p65 overexpression and pharmacological inhibition. Efficacy and safety were ultimately verified in SU-DHL-6 and U2932 xenograft model. Results Z2-A-Z2 demonstrated potent and selective anti-proliferative activity against DLBCL cell lines, achieving an average IC₅₀ of approximately 1.1 µM. This efficacy was 3- to 6-fold superior to arsenic trioxide (ATO), while exhibiting minimal cytotoxicity toward normal PBMCs and B cells. Mechanistically, Z2-A-Z2 induced profound mitochondrial-mediated apoptosis and G2/M cell cycle arrest through a unique dual action of simultaneously triggering catastrophic oxidative stress and critically suppressing the pro-survival NF-κB/IκBα signaling axis. Further investigation revealed a bidirectional regulation where ROS acts upstream to suppress p65 activity, while p65 in turn modulates drug-induced ROS generation. In vivo studies further validated these findings, showing that Z2-A-Z2 resulted in a robust suppression of tumor growth in a xenograft model, accompanied by diminished NF-κB/IκBα activity and increased apoptosis, alongside an excellent safety profile. Conclusion Z2-A-Z2 is a promising organic arsenical with superior efficacy and safety over ATO. Its unique dual-action strategy of simultaneously inducing oxidative stress and critically inhibiting the NF-κB/IκBα signaling axis, positioning it as a strong clinical candidate for effectively treating DLBCL.

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Wei et al. (Mon,) studied this question.

synapsesocial.com/papers/6a0d50cdf03e14405aa9ce5a https://doi.org/https://doi.org/10.1186/s13046-026-03724-4

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