Macrocyclic Proteasome Inhibitors
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Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors. Keywords: Proteasome inhibitor, natural product, macrocycle, argyrin, syringolin, syrbactin, rational drug design, TMC-95A, anticancer agent, medicinal chemistry, glidobactinKeywords:
Anticancer drug
Natural product
Studies have shown that the 26S proteasome is involved in cell cycle control, transcription, DNA repair, immune response and protein synthesis. In the present study, we investigated the antiproliferative effects of the proteasome inhibitor bortezomib and heat shock protein (Hsp)70 inhibitors on the B16F10 melanoma cell line. The IC50 value of bortezomib was found to be 2.46 nM, while that of the Hsp70 inhibitor quercetin was 45 µM in the B16F10 cells. This indicates that bortezomib is more effective than quercetin in inhibiting cell growth. In response to treatment with 10 nM bortezomib for 24 h, cells underwent rounding, shrinkage and detachment. Unexpectedly, such morphological changes were not observed in cells treated with 20 µM quercetin alone, nor in cells treated with bortezomib + quercetin, indicating that quercetin inhibited the cytotoxic effects of bortezomib. Quantitation of cell viability also indicated that quercetin interfered with the cytotoxic effects of bortezomib. However, the combination of quercetin with another proteasome inhibitor, MG132, caused significant cell death as compared to single-agent treatment. A DNA ladder assay also confirmed the inhibitory effect of quercetin on the apoptosis-inducing effect of bortezomib. However, quercetin did not prevent the induction of apoptosis by MG132; on the contrary, it potentiated the apoptosis-inducing effect of MG132. These results suggest that the combination of quercetin with clinically beneficial proteasome inhibitors (except bortezomib) may have increased efficacy in the treatment of cancer. We also tested the combination of two other Hsp70 inhibitors, KNK-437 and schisandrin-B, in combination with bortezomib. Neither of these combinations was more effective than single-agent treatment.
MG132
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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.
Key words:
Mutiple myeloma; Proteasome inhibitor; Drug resistance
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Studies have shown that the 26S proteasome is involved in cell cycle control, transcription, DNA repair, immune response and protein synthesis. In the present study, we investigated the antiproliferative effects of the proteasome inhibitor bortezomib and heat shock protein (Hsp)70 inhibitors on the B16F10 melanoma cell line. The IC50 value of bortezomib was found to be 2.46 nM, while that of the Hsp70 inhibitor quercetin was 45 µM in the B16F10 cells. This indicates that bortezomib is more effective than quercetin in inhibiting cell growth. In response to treatment with 10 nM bortezomib for 24 h, cells underwent rounding, shrinkage and detachment. Unexpectedly, such morphological changes were not observed in cells treated with 20 µM quercetin alone, nor in cells treated with bortezomib + quercetin, indicating that quercetin inhibited the cytotoxic effects of bortezomib. Quantitation of cell viability also indicated that quercetin interfered with the cytotoxic effects of bortezomib. However, the combination of quercetin with another proteasome inhibitor, MG132, caused significant cell death as compared to single-agent treatment. A DNA ladder assay also confirmed the inhibitory effect of quercetin on the apoptosis-inducing effect of bortezomib. However, quercetin did not prevent the induction of apoptosis by MG132; on the contrary, it potentiated the apoptosis-inducing effect of MG132. These results suggest that the combination of quercetin with clinically beneficial proteasome inhibitors (except bortezomib) may have increased efficacy in the treatment of cancer. We also tested the combination of two other Hsp70 inhibitors, KNK-437 and schisandrin-B, in combination with bortezomib. Neither of these combinations was more effective than single-agent treatment.
MG132
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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.
Refractory (planetary science)
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The ubiquitin-proteasome pathway is one of important pathways during selective protein degradation,which participates in many intracellular physiological and biochemical processes.Bortezomib,a kind of proteasome inhibitor,can inhibit cell growth and proliferation,induce cell apoptosis and overcome drug resistance in chemotherapy.The mechanisms of bortezomib on the therapy of multiple myeloma are reviewed in this paper.
Key words:
Multiple myeloma; Proteasome inhibitor, Bortezomib; Therapy
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Multiple myeloma (MM) is a malignant plasma cell disease which occured predominantly in the elderly. In recent years, due to the application of small molecular proteasome inhibitor and immunomodulator, MM has become a chronic disease with good response to new treatments rather than a deadly disease that is lack of effective treatments. However, the occurrence of drug resistance makes MM less likely to be cured, which is one of the biggest challenges in MM clinical treatment. This article will review the mechanisms of acquired resistance to bortezomib in MM, including target genes modification, bypass signaling and so forth.
Key words:
Multiple myeloma; Drug resistance; Bortezomib; Proteasome inhibitor
Plasma Cell Myeloma
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Proteasome inhibitor bortezomib has a very powerful anti-myeloma effect on both preclinical and clinical trails.it has been widely used in the treatment of newly diagnosed,refractory and relapse multiple myeloma.Its side effects were well tolerant and manageable.
Key words:
Multiple myeloma; Protease inhibitor
Refractory (planetary science)
Myeloma protein
Protease inhibitor (pharmacology)
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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 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.
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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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