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Diffuse large B-cell lymphoma (DLBCL), a heterogeneous malignancy characterized by distinct genetic and clinical subtypes, remains a therapeutic challenge despite standard R-CHOP chemotherapy. This study systematically investigated the synergistic anti-tumor efficacy and mechanism of the histone deacetylase inhibitor chidamide (CHI) combined with doxorubicin (DOX) in DLBCL models. Through multimodal experimental approaches including CCK8 proliferation assays, senescence-associated β-galactosidase (SA-β-gal) staining analysis, comet assay for DNA damage quantification, and comprehensive western blotting for molecular mechanism elucidation, we identified a potent synergistic interaction between CHI and DOX. By constructing a xenograft tumor model, the synergistic effect of the two drugs and its mechanism in vivo were confirmed. Our research found that CHI showed cell cycle inhibition and apoptosis induction effects on DLBCL cells. When combined with DOX, both synergistically inhibited the proliferation of DLBCL cells and promoted death of DOX-induced senescent cells. Preliminary mechanism studies revealed that CHI can reduce the level of mutant p53, inhibit cell senescence, and induce irreparable DNA damage in DOX-induced senescent tumor cells, ultimately leading them into programmed apoptosis. Thus, the "One-two punch" strategy increased the sensitivity of p53-mutated DLBCL cells to CHI. In summary, our study demonstrates that CHI synergizes with DOX to suppress DLBCL and presents a promising strategy to augment the therapeutic efficacy of DOX.