The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma

Abstract

Single-agent bortezomib, a potent, selective, and reversible inhibitor of the 26S proteasome, has demonstrated clinical efficacy in relapsed and refractory mantle cell lymphoma (MCL). Objective response is achieved in up to 45% of the MCL patients; however, complete remission rates are low and duration of response proved to be relatively short. These limitations may be overcome by combining proteasome inhibition with conventional chemotherapy. Rational combination treatment and schedules require profound knowledge of underlying molecular mechanisms. Here we show that single-agent bortezomib treatment of MCL cell lines leads to G2/M arrest and induction of apoptosis accompanied by downregulation of EIF4E and CCND1 mRNA but upregulation of p15(INK4B) and p21 mRNA. We further present synergistic efficacy of bortezomib combined with cytarabine in MCL cell lines. Interestingly this sequence-dependent synergistic effect was seen almost exclusively in combination with AraC, indicating that pretreatment with cytarabine, followed by proteasome inhibition, may be the preferred approach.

Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins

“…Table III from our proteomics study indicates that PEO1CarbR cells expressed the highest level of this protein, which may go some way to explaining the preferential sensitisation effect we saw in this cell line (Figure 2). Moreover, the same study demonstrated synergy between chemotherapy and bortezomib, lending support to our findings (41).…”

“…Like many targeted therapies, bortezomib has reported 'off-target' effects. The eukaryotic initiation factor 4A-1 (EIF4E1) has been shown to be targeted by bortezomib in haematological malignancies, giving rise to G 2 M blockade (41). Table III from our proteomics study indicates that PEO1CarbR cells expressed the highest level of this protein, which may go some way to explaining the preferential sensitisation effect we saw in this cell line (Figure 2).…”

Efficacy of the GemOx‐R regimen leads to the identification of Oxaliplatin as a highly effective drug against Mantle Cell Lymphoma

“…For instance, bendamustine has shown good results in combination with rituximab (Rummel et al, 2013) or with cytarabine and rituximab (R-BAC) in MCL patients not eligible for intensive therapy (Visco et al, 2013) (100% ORR, 95% CR). The synergy of the proteasome inhibitor bortezomib and cytarabine has been reported in two case reports (Weigert et al, 2007) and in MCL cell lines (Weigert et al, 2007;Hutter et al, 2012). The synergy of the proteasome inhibitor bortezomib and cytarabine has been reported in two case reports (Weigert et al, 2007) and in MCL cell lines (Weigert et al, 2007;Hutter et al, 2012).…”

Mitotic catastrophe and cell cycle arrest are alternative cell death pathways executed by bortezomib in rituximab resistant B-cell lymphoma cells

“…BTZ has been shown to induce apoptosis, [14–16] to arrest cell proliferation,17,18 inhibit angiogenesis,19,20 and disrupt the cell-cycle in cancer cells [15, 21, 22]. BTZ's contribution to apoptosis in lymphoma depends on the transcription regulation and/or inhibition of the proteasome degradation of various anti- or pro-apoptotic proteins [8].…”