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A Promising Natural G6PD Inhibitor for Potential Therapeutic Strategies in DLBCL

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has a high degree of clinical and biological heterogeneity. Although most patients can be cured with R-CHOP immunochemotherapy,30-40% of patients have progression or recurrence after treatment. Therefore, there is an urgent need to find new treatments to improve the survival rate of this group of patients. Natural small molecule drugs have unique advantages as anticancer agents due to their low toxicity and multiple targets. This project aims to explore potentially effective natural compounds as new therapeutic strategies for DLBCL. We found that Cinobufagin is a potentially effective therapeutic agent for DLBCL. Glucose 6 phosphate dehydrogenase (G6PD), a risk factor for poor prognosis in DLBCL, was a direct target of Cinobufagin. By inhibiting the enzyme activity of G6PD, Cinobufagin could inhibit DNA synthesis and the production of reductive NADPH, thereby inducing ROS accumulation and apoptosis of DLBCL cells. Our findings provide new strategies for the treatment of DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254385 | GEO | 2024/07/31

REPOSITORIES: GEO

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Project description:Purpose: Despite recent advances in the treatment of patients with aggressive lymphomas, still a significant fraction of patients will succumb to their disease. Thus, novel therapeutic strategies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Experimental Design: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Overall, three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 2/11 cell lines were primarily sensitive to tafasitamab and 2/11 were predominantly sensitive to rituximab treatment, the combination of tafasitamab and rituximab resulted in enhanced cell death in 7/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combinatorial approach of the two antibodies resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusions: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to antibody mono treatment in models of aggressive B-cell lymphoma in vitro and in vivo. Translational Relevance: The immunochemotherapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab and rituximab target the B-cell surface proteins CD19 and CD20, respectively, and both antibodies feature overlapping modes of action , namely direct cytotoxicity, ADCC and ADCP. In this study, we show that the combination of tafasitamab and rituximab had additive and synergistic efficacy both in vitro and in vivo. Our findings shed new light on the underlying mechanism of the combination of both antibodies and lay the ground to translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

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A Promising Natural G6PD Inhibitor for Potential Therapeutic Strategies in DLBCL

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