Publication Date
1-1-2024
Journal
PLoS One
DOI
10.1371/journal.pone.0289902
PMID
38683834
PMCID
PMC11057735
PubMedCentral® Posted Date
4-29-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Lymphoma, Mantle-Cell, Animals, Humans, Mice, Cell Line, Tumor, Adenine, Piperidines, Antineoplastic Agents, Pyrimidines, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Pyrazoles, Female
Abstract
Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biology Commons, Genetic Phenomena Commons, Hematology Commons, Hemic and Lymphatic Diseases Commons, Oncology Commons
