Damnacanthus giganteus extract block diffuse large b-cell lymphoma proliferation and EMT by regulating mitochondrial dysfunction and glycolysis

Background: In non-Hodgkin's lymphoma, diffuse large b-cell lymphoma (DLBCL) is one of the most prevalent and commonly diagnosed subtypes. There is a need to develop more effective drugs since the currently approved drugs still have limitations.

Methods: DLBCL cell lines were intervened with different concentrations of Damnacanthus giganteus extract (DGE). The malignant phenotype of DLBCL cells was detected by CCK-8, colony formation assay, AnnexinV-PI double staining assay, and Transwell. The effect of DGE on the in vivo growth of DLBCL cells was assessed by nude mice transplantation tumor assay and immunohistochemistry. Cellular mitochondrial function was assessed by measuring mitochondrial ROS levels, MMP, and ATP production, and glycolysis was assessed by determining glucose uptake and lactate production. The changes of epithelial-mesenchymal transition (EMT) markers were evaluated via Western blot.

Results: Intervention with low-toxicity concentrations of DGE significantly inhibited proliferative capacity and clonogenic potential in DLBCL cells while concurrently enhancing Apoptosis and cisplatin sensitivity. DGE treatment also suppressed migratory and invasive behaviors, accompanied by downregulation of mesenchymal markers N-Cadherin and Vimentin. In vivo studies confirmed therapeutic efficacy, with DGE monotherapy showing marked tumor growth suppression and synergistic activity with cisplatin. Mechanistically, DGE exacerbated mitochondrial dysfunction and suppressed glycolysis. This mitochondrial impairment phenotype elicited by DGE treatment was recapitulated using the mitochondrial complex I inhibitor Rotenone, which similarly induced proliferation inhibition and EMT modulation. Furthermore, the ROS scavenger N-acetylcysteine partially rescued DGE-induced cellular alterations, including proliferation and EMT suppression.

Conclusion: ‌Our study demonstrates for the first time that DGE effectively suppresses tumor proliferation and EMT during DLBCL progression. These antitumor effects appear to be mediated through modulation of mitochondrial function and glycolysis. These findings position DGE as a promising novel therapeutic candidate for DLBCL treatment, meriting immediate clinical translation and further evaluation.

Damnacanthus giganteus extract; Diffuse large b-cell lymphoma; Epithelial-to-mesenchymal transition; Glycolysis; Mitochondrial dysfunction; Proliferation.