Combination of atiprimod and the proteasome inhibitor bortezomib induces apoptosis of mantle cell lymphoma in vitro and in vivo

The proteasome inhibitor bortezomib (BTZ) is known to be chemotherapeutic in relapsed or refractory mantle cell lymphoma (MCL). Atiprimod (ATI), a novel cationic amphophilic compound, has been tested in clinical trials in multiple myeloma (MM). We sought to evaluate the effect of an ATI–BTZ combination on MCL and to elucidate its therapeutic mechanisms. The ATI and BTZ combination significantly inhibited growth and induced apoptosis of both cultured MCL cell lines and freshly isolated tumor cells from patients with refractory or relapsed MCL. However, the combination yielded lower cytotoxicity in normal peripheral blood mononuclear cells (PBMC). Furthermore, ATI and BTZ induced apoptosis via two different signaling pathways. More significantly, ATI and BTZ markedly delayed tumor growth and prolonged survival in MCL-bearing NOD–SCID mice. Our results demonstrate that ATI and BTZ confer significant therapeutic effects in MCL in vitro and in vivo and should therefore be investigated in a clinical trial in patients with relapsed or refractory MCL.