Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib
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The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy.Mantle cell lymphoma is a distinct subtype of non-Hodgkin lymphoma (NHL) that remains incurable with the shortest survival time. Bortezomib is the first proteasome inhibitor used for the treatment of hematological malignant diseases, such as multiple myeloma and relapse or refractory mantle cell lymphoma (MCL). Investing the mechanism of bortezomib for MCL, including modulation of cell cycle, the influence of cell apoptosis, the disturbance of the MCL microenvironment and the cooperative action with other antineoplastic drugs, is helpful to make the treatment strategy for MCL.
Key words:
Bortezomib; Lymphoma,mantle-cell; Molecular mechanism of action
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Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion ofbone marrow plasmacytes.It accounts for 10 ％ of all hematological malignancies.The proteasome,an intracellular enzyme complex that degrades ubiquitin-tagged proteins to regulate protein levels within the cell,plays an important role in maintaining cellular homeostasis.Proteasome inhibitors proved to be significantly effective in the clinical treatment of MM.In recent years,the application of the proteasome inhibitor has led to increased survival rates in MM patients.Bortezomib is the first proteasome inhibitor that has been approved by the US Food and Drug Administration due to its ability to reversibly inhibit the 26 s proteasome functions.Despite the fact that Bortezomib improves medical treatment,many patients experience difficulty responding to this drug and some patients who do respond eventually relapse.These results have led researchers to investigate new proteasome inhibitors with mechanisms different from those of Bortezomib.Some drugs that bind to the active site of the proteasome and irreversibly inhibit the complex have recently been developed and are currently being tested in advanced clinical trials.Here,we will elaborate on the proteasome inhibitors targeting MM and focus on newly discovered inhibitors that may overcome the resistance to Bortezomib.
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Mutiple myeloma; Proteasome inhibitor; Drug resistance
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The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes' active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a low-nanomolar IC(50) - suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.
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The 26S proteasome is a multicatalytic enzyme responsible for degradation of a large fraction of intracellular proteins. Targeting the proteasome activity is a rational and novel strategy for cancer therapy that can lead to cell death for transformed cells. Today, bortezomib, a first-in-class proteasome inhibitor, has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma. Since bortezomib has also shown to induce chemosensitization, the drug is utilized for combination with a variety of chemotherapeutics. In this review, we provide an overview of the current state of the use of bortezomib and second generation proteasome inhibitors.
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Mantle cell lymphoma (MCL) is a hematological malignancy with unfavorable prognosis. Bortezomib, a potent, selective and reversible inhibitor of the 26S proteasome, was shown to be active in MCL and is currently implemented in therapeutic combinations. Single-agent bortezomib has demonstrated clinical efficacy in relapsed and refractory MCL with objective response in up to 47% of the patients. However, complete remission rates are low and duration of response is relatively short. In previously untreated patients, the addition of bortezomib to induction chemotherapy is also promising. Further evaluation of bortezomib alone or in combination with other drugs for the treatment of MCL is warranted to improve the quality of life and survival of patients. This review explores bortezomib as therapy in patients with MCL.
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Probing the Specificity and Activity Profiles of the Proteasome Inhibitors Bortezomib and Delanzomib
The ubiquitin proteasome system is an attractive pharmacological target for the treatment of cancer. The proteasome inhibitor bortezomib has been approved for the treatment of multiple myeloma and mantle cell lymphoma but is associated with substantial adverse effects and the occurrence of resistance, underscoring the continued need for novel proteasome inhibitors. In this study, bortezomib and the novel proteasome inhibitor delanzomib were compared for their ability to inhibit proteasome activity using both fluorogenic substrates and a recently developed fluorescent proteasome activity probe. Bortezomib and delanzomib were equipotent in inhibiting distinct subunits of the proteasome in a panel of cell lines in vitro. In a preclinical multiple myeloma model, both inhibitors inhibited the proteasome in normal tissues to a similar extent. Tumor proteasome activity was inhibited to a significantly higher extent by delanzomib (60%) compared to bortezomib (32%). In addition, delanzomib was able to overcome bortezomib resistance in vitro. The present findings demonstrate that proteasome activity probes can accurately monitor the effects of proteasome inhibitors on both normal and tumor tissues in preclinical models and can be used as a diagnostic approach to predict resistance against treatment with proteasome inhibitors. Furthermore, the data presented here provide rationale for further clinical development of delanzomib.
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The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. Recently, we demonstrated that bortezomib eliminates autoreactive plasma cells in SLE mice, thereby representing a promising novel treatment for antibody-mediated diseases. Here, we investigated the effect …
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Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NF-kB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the AKT pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NF-kB and phosphorylated AKT depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
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Research progress of bortezomib therapy in patients with relapsed or refractory mantle cell lymphoma
Currently refractory and relapsed mantle cell lymphoma (MCL) continues to develope a poor prognosis, and the treatment remains a significant clinical challenge. The use of bortezomib in clinic provides a novel method for the treatment of refractory and relapsed MCL. This review summarizes the mechanism and efficiency of bortezomib in the treatment of MCL and the strategies for overcome of bortezomib resistance.
Key words:
Lymphoma, mantle-cell; Bortezomib; Therapy
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