Arsenic trioxide rewires mantle cell lymphoma response to bortezomib

Abstract

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.

Induction of autophagy and autophagy‐dependent apoptosis in diffuse large B‐cell lymphoma by a new antimalarial artemisinin derivative, SM1044

“…Nude mice were subcutaneously inoculated in the right flank with 1.5 × 10 7 SU‐DHL‐4 cells suspended in 100 μ L 1× PBS. The two largest perpendicular axes were measured with standard calipers, and tumor volume was calculated using the following formula: (length) × (width) 2 /2 as previously reported . When tumors reached 5 mm in the length, mice were randomly separated into vehicle control (normal saline, n = 11) or SM1044 (5 mg/kg per day, n = 12) treatment groups.…”

Arsenic-Based Anticancer-Combined Therapy: Novel Mechanism Inducing Apoptosis of Cancer Cells

“…In acute lymphoblastic leukemia (ALL), low-dose ATO sensitized glucocorticoid-resistant ALL cells to dexamethasone via an Akt-dependent pathway [113]. Jung et al and Zhao et al independently showed the synergistic anticancer effects of ATO with BOR in mantle cell lymphoma, which is an aggressive and highly incurable B-cell non-Hodgkin lymphoma [114,115]. Ding et al recently reported that combined treatment of ATO with cucurbitacin B, an effective component of the dichloromethane extraction from Trichosanthes kirilowii maxim, synergistically enhances apoptosis by inhibiting STAT3 phosphorylation in Burkitt's lymphoma cell lines both in vitro and in vivo [116].…”

The preclinical discovery and development of bortezomib for the treatment of mantle cell lymphoma

“…In MCL xenograft studies using SCID mice, the drug combination treatment prevents tumor development and prolongs animal survival [61]. Arsenic Trioxide (ATO), which has been shown to upregulate pro-apoptotic proteins and induce apoptosis in MCL through downregulation of the NFκB pathway, also displays synergy with BTZ [62–63]. This has been demonstrated in multiple MCL cell lines (Jeko-1, SP-53, Mino, and REC-1) and primary patient samples.…”