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Antitumor effects of rafoxanide in diffuse large B cell lymphoma via the PTEN/PI3K/Akt and JNK/c-Jun pathways
Wan He1, Zhijian Xu2, Dongliang Song1
1Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Aims:
Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive lymphoid malignancies, which remains incurable, thus warranting the development of new therapies. Our previous study determined that rafoxanide is very effective in treating multiple myeloma (MM). In the present study, we tried to evaluate the effects of rafoxanide on DLBCL, as well as the potential underlying molecular mechanisms.
Main Methods:
We used CCK-8 assay and flow cytometry to assess cell viability and apoptosis. The proteins and pathways associated with apoptosis and proliferation were evaluated through western blot, and xenograft mice were used as the experimental animal model. We also used the TUNEL assay and immunofluorescence for further analyses.
Key Findings:
Treatment with different doses of rafoxanide significantly inhibited cell viability and apoptosis. Additionally, the compound induced cell cycle arrest, reduced mitochondrial membrane potential (Δψm), and stimulated reactive oxygen species (ROS) generation without the influence of normal peripheral blood monocytes (PBMCs). As expected, rafoxanide played a role in regulating these proteins and the PTEN/PI3K/AKT and JNK/c-Jun pathways. Furthermore, immunofluorescence and western blot results showed that rafoxanide upregulated H2AX phosphorylation and then inhibited DNA repair in DLBCL. In the xenograft mouse model, tumor volumes were reduced after intraperitoneal injection with rafoxanide. We also observed that TUNEL positive cells were remarkably increased in rafoxanide-treated tumor tissues.
Significance:
These results collectively provide a novel choice to regular treatment for DLBCL patients with poor prognosis.
Insights
Rafoxanide effectively treats diffuse large B-cell lymphoma (DLBCL) by inhibiting cell viability and inducing apoptosis. This novel therapy shows promise for DLBCL patients with poor prognoses, reducing tumor growth in preclinical models.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid malignancy with limited treatment options.
- Previous research demonstrated rafoxanide's efficacy in treating multiple myeloma (MM).
Purpose of the Study:
- To evaluate the anti-cancer effects of rafoxanide on DLBCL.
- To elucidate the molecular mechanisms underlying rafoxanide's action in DLBCL.
Main Methods:
- Cell viability and apoptosis assessed via CCK-8 assay and flow cytometry.
- Western blot used to analyze protein and pathway regulation.
- Xenograft mouse models employed for in vivo efficacy studies, with TUNEL and immunofluorescence assays.
Main Results:
- Rafoxanide significantly inhibited DLBCL cell viability and induced apoptosis.
- The compound caused cell cycle arrest, reduced mitochondrial membrane potential, and increased reactive oxygen species (ROS).
- Rafoxanide modulated PTEN/PI3K/AKT and JNK/c-Jun pathways, upregulated H2AX phosphorylation, and inhibited DNA repair, leading to reduced tumor volume in vivo.
Conclusions:
- Rafoxanide demonstrates significant anti-DLBCL activity through multiple molecular mechanisms.
- These findings suggest rafoxanide as a potential novel therapeutic agent for DLBCL.
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