Bortezomib (PS-341)
(Synonyms: 硼替佐米; PS-341; LDP-341; NSC 681239) 目录号 : GC17644
硼替佐米(PS-341)作为一种具有抗肿瘤活性的二肽硼酸蛋白酶体抑制剂,可通过靶向苏氨酸残基,有效抑制Ki为0.6 nM的20S蛋白酶体。.
Cas No.:179324-69-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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| Cell experiment [1]: | |
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Cell lines |
bone marrow (BM) cells |
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Preparation Method |
Proliferation inhibition analysis of DCs in bone marrow (BM) cells was treated with 10 nM - 50 nM Bortezomib for 24 hours, 48 hours and 72 hours, respectively. |
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Reaction Conditions |
10 nM - 50 nM; for 24 hours, 48 hours and 72 hours |
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Applications |
The proliferation of DCs was significantly inhibited when treating with Bortezomib at 10 nM for 24 hours compared to control cells. The inhibition was significantly potentiated with higher concentrations of Bortezomib. Compared to untreated cells, less than 40% cells were detected when treated with Bortezomib at 50 nM for 24 hours. The inhibition of Bortezomib to DCs is both dose- and time-dependent. |
| Animal experiment [2]: | |
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Animal models |
Six-week-old BALB/c female athymic nude mice |
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Preparation Method |
Five days after HCS-2/8 and OUMS-27 cells were injected subcutaneously into the right armpit of nude BALB/c mice, the mice were randomly divided into two groups and intraperitoneally administered DMSO or botezomib at a dose of 0.5 mg/kg every other day for 30 days. The volume of xenografts was measured every five days (tumor volume = (length × width2)/2). |
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Dosage form |
0.5 mg/kg; s.c. |
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Applications |
Bortezomib administration was very effective in inhibiting tumor growth in vivo throughout the course of treatment, resulting in decreased tumor size. |
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References: | |
Bortezomib (PS-341), as a dipeptide boronic acid proteasome inhibitor with antitumor activity, can potently inhibiit 20S proteasome with Ki of 0.6 nM by targeting a threonine residue[1].
In vitro, Bortezomib can retain NF-kappaB in the cytoplasm and inhibit cell growth with IC50 of 22.5 nM, in a dose/time-dependent way[2]. Bortezomib inhibited growth and induced apoptosis of PEL (primary effusion lymphomas) cell lines with IC50 values of 3.4-5.0 nM[3].
In vitro, 1 µmol/L-10 nmol/L bortezomib can activate the Akt pathway via increased SRC-3 (Steroid receptor coactivator-3)[4]. In vitro, 20 nM bortezomib induces apoptotic cell death and promotes G0/G1 phase arrest[5].
In vivo, BALB/c mice were treated with 1 mg/kg bortezomib intraperitoneally once weekly for 2 weeks increased phosphorylation of JNK (c-Jun N-terminal kinase) and extracellular signal-regulated protein kinase (ERK) in the spinal cord[6]. In vivo, mice were treated with bortezomib (2 mg/kg, i.v.) on Day1 and Day4 each week for continuous 4 weeks. bortezomib-treated mice showed enhanced mechanical hyperalgesia, decreased tail nerve conduction and sciatic nerve demyelination[7].
[1] Adams J, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22.
[2] Galimberti S, et al. PS-341 (Bortezomib) inhibits proliferation and induces apoptosis of megakaryoblastic MO7-e cells. Leuk Res. 2008 Jan;32(1):103-12.
[3] An J, et al. Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia. 2004 Oct;18(10):1699-704.
[4] Ayala G, et al. Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt. Clin Cancer Res. 2008 Nov 15;14(22):7511-8.
[5] Bao X, et al. Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma. Int J Oncol. 2017 Feb;50(2):477-486.
[6] Tsubaki M., et al. Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation. Am. J. Cancer Res. 2018;8:1239-1248.
[7] Wu Z, et al. Lysosomal dysfunction in Schwann cells is involved in bortezomib-induced peripheral neurotoxicity. Arch Toxicol. 2023 May;97(5):1385-1396.
References:
硼替佐米(PS-341)作为一种具有抗肿瘤活性的二肽硼酸蛋白酶体抑制剂,可通过靶向苏氨酸残基,有效抑制Ki为0.6 nM的20S蛋白酶体[1]。
在体外,硼替佐米可将 NF-kappaB 保留在细胞质中,并以剂量/时间依赖性的方式抑制细胞生长(IC50=22.5 nM)[2]。硼替佐米能抑制 PEL(原发性渗出性淋巴瘤)细胞系的生长并诱导其凋亡,IC50 值为 3.4-5.0 nM[3]。
在体外,1 µmol/L-10 nmol/L 硼替佐米可通过增加 SRC-3(类固醇受体辅激活剂-3)激活 Akt 通路[4]。在体外,20 nM 硼替佐米可诱导细胞凋亡并促进 G0/G1 期停滞[5]。
在体内,BALB/c 小鼠每周一次腹腔注射 1 毫克/千克硼替佐米,连续 2 周后,脊髓中JNK(c-Jun N端激酶)和细胞外信号调节蛋白激酶(ERK)的磷酸化增加[6]。在体内,每周第1天和第4天用硼替佐米(2 mg/kg,静脉注射)治疗小鼠,连续4周。经硼替佐米处理的小鼠表现出机械性痛觉减退、尾神经传导减弱和坐骨神经脱髓鞘[7]。
| Cas No. | 179324-69-7 | SDF | |
| 别名 | 硼替佐米; PS-341; LDP-341; NSC 681239 | ||
| 化学名 | [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid | ||
| Canonical SMILES | B(C(CC(C)C)NC(=O)C(CC1=CC=CC=C1)NC(=O)C2=NC=CN=C2)(O)O | ||
| 分子式 | C19H25BN4O4 | 分子量 | 384.24 |
| 溶解度 | ≥ 19.212mg/mL in DMSO | 储存条件 | 4°C, protect from light |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6025 mL | 13.0127 mL | 26.0254 mL |
| 5 mM | 0.5205 mL | 2.6025 mL | 5.2051 mL |
| 10 mM | 0.2603 mL | 1.3013 mL | 2.6025 mL |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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The safety of bortezomib for the treatment of multiple myeloma
There is now 16 years' worth of established results of various trials demonstrating the bortezomib efficiency in the treatment of multiple myeloma. Over this time, the introduction of bortezomib has been a major break through in the treatment of multiple myeloma. Bortezomib can be administered in the outpatient setting with manageable toxicities. Areas covered: A literature search was carried out using PubMed and Google Scholar. This review gives an overview of the critical role of the bortezomib in multiple myeloma and provides a comprehensive summary of key clinical benefit and safety data with the bortezomib. Initial toxicity profile has improved dramatically with introduction of subcutaneous administration and also, implementation of guidelines for early recognition and treatment. Triplet and quadruplets of bortezomib with agents possessing similar toxicities constitute a challenge. Expert opinion: Bortezomib is an important part of current anti-myeloma therapy with a good clinical efficacy and manageable side effects. Although gastrointestinal disturbances and fatigue are the most common adverse effects, peripheral neuropathy and thrombocytopenia are the key dose-limiting toxicities of bortezomib-based combination regimens. Since these combinations are more effective, with faster disappearance of disease related symptoms and anti-inflammatory effects of bortezomib toxicities were not found to be augmented.
Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib
Proteasome inhibitors disrupt multiple pathways in cells and the bone marrow microenvironment, resulting in apoptosis and inhibition of cell-cycle progression, angiogenesis, and proliferation. Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma after one prior therapy. It is also effective in other plasma cell disorders and non-Hodgkin lymphomas. The main mechanism of action of bortezomib is to inhibit the chymotrypsin-like site of the 20S proteolytic core within the 26S proteasome, thereby inducing cell-cycle arrest and apoptosis. The pharmacokinetic profile of intravenous bortezomib is characterized by a two-compartment model with a rapid initial distribution phase followed by a longer elimination phase and a large volume of distribution. Bortezomib is available for subcutaneous and intravenous administration. Pharmacokinetic studies comparing subcutaneous and intravenous bortezomib demonstrated that systemic exposure was equivalent for both routes; pharmacodynamic parameters of 20S proteasome inhibition were also similar. Renal impairment does not influence the intrinsic pharmacokinetics of bortezomib. However, moderate or severe hepatic impairment causes an increase in plasma concentrations of bortezomib. Therefore, patients with moderate or severe hepatic impairment should start at a reduced dose. Because bortezomib undergoes extensive metabolism by hepatic cytochrome P450 3A4 and 2C19 enzymes, certain strong cytochrome P450 3A4 inducers and inhibitors can also alter the systemic exposure of bortezomib. This article critically reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of bortezomib at various dosing levels and routes of administration as well as in specific patient subsets. In addition, we discuss the clinical efficacy and safety of bortezomib.
Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy
Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.
Transplantation and immunosuppression: a review of novel transplant-related immunosuppressant drugs
Immunosuppressive drugs used in the transplantation period are generally defined as induction and maintenance therapy. The use of immunosuppressants, which are particularly useful and have fewer side effects, decreased both mortality and morbidity. Many drugs such as steroids, calcineurin inhibitors (cyclosporine-A, tacrolimus), antimetabolites (mycophenolate mofetil, azathioprine), and mTOR inhibitors (sirolimus, everolimus) are used as immunosuppressive agents. Although immunosuppressant drugs cause many side effects such as hypertension, infection, and hyperlipidemia, they are the agents that should be used to prevent organ rejection. This shows the importance of individualized drug use. The optimal immunosuppressive therapy post-transplant is not established. Therefore, discovering less toxic but more potent new agents is of great importance, and new experimental and clinical studies are needed in this regard.Our review discussed the mechanism of immunosuppressants, new agents' discovery, and current therapeutic protocols in the transplantation.
Bortezomib for the treatment of multiple myeloma
Background: Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.
Objectives: We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD).
Search methods: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).
Selection criteria: We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.
Data collection and analysis: Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.
Main results: We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.
Authors' conclusions: This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.