Bezafibrate and medroxyprogesterone acetate target resting and CD40L-stimulated primary marginal zone lymphoma and show promise in indolent B-cell non-Hodgkin lymphomas.

B cell non-Hodgkin lymphomas (B-NHLs) are the most common adult hematological cancers and many remain incurable. Development of chemotherapy regimens is confounded by the prevalence of B-NHL in older, frailer patients and the chemo-protective tumor microenvironment. Although biological therapies such as rituximab have significantly improved outcomes and selective kinase inhibitors are showing promise, the rate of new drug discovery remains disappointing, the treatments expensive and long-term benefits uncertain. An alternative strategy is redeployment of available, inexpensive and non-toxic drugs. Here, we demonstrate the antiproliferative and mitochondrial superoxide (MSO) driven pro-apoptotic activities of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against B-NHL cells, with a bias toward MZL, in the presence and absence of the microenvironmental signal CD40L. Our study is the first to confirm the presence of CD40L within the lymph node of B-NHL and its capacity to drive B-NHL proliferation. These findings implicate BEZ + MPA as a potential therapeutic strategy in B-NHL.