COX-2 independent effects of Celecoxib sensitize Lymphoma B cells to TRAIL-mediated apoptosis
Menée in vitro, cette étude met en évidence des mécanismes par lesquels le celecoxib, un anti-inflammatoire non stéroïdien, favorise l'activité apopotique d'une molécule cytotoxique (TRAIL) dans les lymphomes à cellules B
Purpose: Despite therapeutic advances, Non-Hodgkin lymphomas (NHL) remain incurable. They form a group of neoplasms strongly dependent on their inflammatory microenvironment, which plays an important supportive role in tumor B-cell survival and in the resistance to anti-tumor immune response. New therapies must consider both tumor cells and their surrounding microenvironment Experimental Design: Stromal cells, derived from bone marrow or lymph nodes, and B cells from follicular lymphoma patients were co-cultured or cultured alone with Celecoxib treatment, a non-steroidal anti-inflammatory drug and/or TRAIL, a promising cytotoxic molecule for cancer therapy. Results: In this study, we show that follicular lymphoma (FL) stromal cells produce large amounts of PGE2. This production is abrogated after Celecoxib treatment, targeting the COX-2 isoenzyme involved in PGE2 synthesis. Furthermore, we demonstrate that Celecoxib increases apoptosis in NHL B-cell lines and in primary FL B-cells co-cultured with stromal cells, but independently of the PGE2/COX-2 axis. Finally, Celecoxib increases the apoptotic activity of TRAIL. We provide evidence that Celecoxib affects proliferation and sensitizes NHL B-cell lines to apoptosis through COX-2 independent effects by slowing down the cell cycle and decreasing the expression of survival proteins, such as Mcl-1. Conclusions: These data suggest new potent strategies for NHL therapy combining drugs targeting both tumour B cells and survival signals provided by the tumor microenvironment.