Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Abstract

Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

Formulation, Development, and In Vitro Evaluation of a CD22 Targeted Liposomal System Containing a Non-Cardiotoxic Anthracycline for B Cell Malignancies

“…Treatment with LCCTLA reduced the expression of c-myc in a time-dependent manner as shown in Figure 8 A. Similar results were also demonstrated by Edwards et al [ 45 ].…”

“…It is a protein kinase C (PKC) activating agent that displays superiority over doxorubicin [ 41 ]. It functions by a completely different mechanism of action compared to doxorubicin which has been or is under study by four groups, Cekanova et al, Xie et al, He et al and Lothstein et al [ 40 , 43 , 44 , 45 ]. AD 198 does not display any significant organ toxicities and is less myelosuppressive compared to doxorubicin [ 39 ].…”

Elevated Choline Kinase α–Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes

“…Mouse B lymphoma cell lines (1 3 10 5 cells per well) and human MM or B lymphoma cell lines (3 3 10 4 cells per well) were plated in 96-well plates in the absence or presence of serial dilutions of Chka inhibitors. At the indicated time point after treatment, cell viability and proliferation were measured using the MTT assay, as described (41). Possible influences caused by direct MTTinhibitor interactions were excluded by studies in a cell-free system.…”

Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis

“…Preclinical data demonstrated that all human myeloma cell lines sensitive to venetoclax were restricted to the Cyclin D1 (CCND1) subgroup (80% harboring t (11;14)) and expressed elevated BCL-2:myeloid cell leukemia-1 (MCL-1) ratios 29 . High expression of MCL-1 leads to venetoclax resistance, however, this can be overcome with the addition of bortezomib, which is known to inhibit MCL-1 [30][31][32] . Dexamethasone favorably alters sensitivity to venetoclax by increasing expression of both BCL-2 and BCL-2-like protein 11 (Bim) and shifting binding of Bim to BCL-2 33 .…”