Arsenic trioxide rewires mantle cell lymphoma response to bortezomib.

Although most of the mantle cell lymphoma (MCL) patients initially responded well to bortezomib (BTZ), the dose-dependent toxicities have greatly limited the application of BTZ to MCL. To investigate the efficacy and mechanism of arsenic trioxide (ATO) with BTZ in inducing apoptosis of MCL cells, two MCL cell lines, along with primary cells from MCL patients (n = 4), were used. Additionally, the NOD-SCID mice xenograft model of Jeko-1 cells was established to study the anti-MCL mechanisms in an in vivo setting. ATO treatment highly improved BTZ capacity to inhibit proliferation and induce apoptosis of MCL cells. Furthermore, the interaction of Noxa and Mcl-1 leads Bak to release from Mcl-1 or from Bcl-xl, which could further activate Bak and Bax and then induce cell apoptosis. We also found that when lower doses of BTZ were used in combination with ATO, more effective proapoptotic effects in both the cell lines and the primary cells were obtained compared to the effects of BTZ used alone at higher doses. Simultaneously, the combination of these two drugs delayed the tumor growth in mice more effectively than BTZ alone. The cooperative anti-MCL effects of this combination therapy both in vitro and in vivo strongly provided a new strategy to the clinical treatment of MCL.