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The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.

Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in

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… The boronic acid is responsible for the actual inhibition, ensuring an increased specificity for the proteasome. … Further stabilization of the tetrahedral boronate adduct comes from a second acidic boronate hydroxyl moiety, which works as a catalytic proton acceptor and is H-bridged to the N-terminal threonine amine atom. …

Integrative Hematology: State of the Art.

Blood cancers are a group of diseases with thus far frequently poor prognosis. Although many new drugs, including target therapies, have been developed in recent years, there is still a need to expand our therapeutic armamentarium to better deal with these diseases. Integrative hematology was conceived as a discipline that enriches the patient's therapeutic possibilities with the use of supplements, vitamins and a nutritional approach aiming at improving the response to therapies and the clinical outcome. We will analyze the substances that have proved most useful in preclinical and clinical s

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… Although EGCG is able to inhibit the proteasome, this would not occur in the presence of bortezomib; EGCG inhibition of bortezomib could be explained by its binding to bortezomib’s boronic acid [ 96 ]. … Due to the interaction with the boronic acid group of bortezomib and the consequent reduction in the activity of the drug, the use of quercetin during therapy with a proteasome inhibitor should be avoided [ 111 ]. …

Complementary and alternative medicine (CAM) supplements in cancer outpatients: analyses of usage and of interaction risks with cancer treatment.

PurposeThe aim of our study was to analyze the use of complementary and alternative medicine (CAM) supplements, identify possible predictors, and analyze and compile potential interactions of CAM supplements with conventional cancer therapy.MethodsWe included outpatient cancer patients treated at a German university hospital in March or April 2020. Information was obtained from questionnaires and patient records. CAM-drug interactions were identified based on literature research for each active ingredient of the supplements consumed by the patients.Results37.4% of a total of 115 patients consu

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… Int J Mol Sci 17(4):537. 10.3390/ijms17040537 27070596 10.3390/ijms17040537 PMC4848993 Golden EB Lam PY Kardosh A Gaffney KJ Cadenas E Louie SG Petasis NA Chen TC Schönthal AH Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors Blood 2009 … 113 23 5927 5937 10.1182/blood-2008-07-171389 19190249 Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schönthal AH (2009) Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. …

Minor clone provides a reservoir for relapse in multiple myeloma.

Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations

Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells.

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappaB pathway and

Novel molecular targeted therapies for refractory thyroid cancer.

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic

[Proteasome inhibitors].

INTRODUCTION: Proteasome is involved in cell cycle and apoptosis regulation. Its deregulation could participate to oncogenesis. EXEGESIS: Bortezomib is the first proteasome inhibitor to reach clinical development. Its main adverse events are asthenia, thrombocytopenia and cumulative neurotoxicity which can limits long term use. As single agent, bortezomib displays antitumoral effects in refractory multiple myeloma and mantle cell lymphoma but has only modest activity in solid tumors. Preclinical data suggest that bortezomib could enhance antitumor activity of cytotoxics. CONCLUSION: Proteaso

Концептуализация комплексного ухода за многими миеломами: роль питания, дополнительных услуг и дополнительных услуг.

Множественная миелома (ММ) — вторая по распространенности гематологическая гелингология, масштабы которой в последние годы значительно возросли. Прогноз ММ радикально изменился с введением новых лекарственных средств, повышающих ожидаемую продолжительность жизни; рецидивы являются обычным явлением во время болезни и характеризуются увеличением числа отказов от лечения. Кроме того, пациенты ММ сталкиваются с проблемами, связанными с качеством жизни, в то время как обычное лечение может быть ограничено. Это включает боль в костях и диализ из-за осложнений острой почечной недостаточности. Поэтому

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… with the boronic acid of the molecule appears to be the mechanism underlying this inhibitory mechanism [ 59 ]. … Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113:5927–5937. doi: 10.1182/blood-2008-07-171389. 60. Wang Q., Li J., Gu J., Huang B., Zhao Y., Zheng D., Ding Y., Zeng L. …

Высоко избирательная и верзольная платформа для визуализации липаса Моноацилглицерол.

Monoacylglycerol Lipase (MAGL) — ключевой фермент для прекращения сигнала в эндоканнабиноидной системе (ECS). Ингибиция MAGL приводит к косвенной активации каннабиноидных рецепторов, что дает уникальные преимущества для лечения, например, множественных склерозов, эпилепсии и других неврологических расстройств. Технологии молекулярной съемки являются ценными инструментами, позволяющими преодолеть нынешнее плохое понимание распределения и роли MAGL в пато- и физиологических процессах в рамках сигнала ECS. В этой связи мы представляем информацию о проектировании, синтезе и подтверждении высокосел

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… The vinyl boronic acid pinacol (Bpin) ester 17 was generated from the respective ketone via a Boron‐Wittig olefination[ 47 , 48 ] using bis[(pinacolato)boryl]‐methane. …

Motexafin gadolinium injection for the treatment of brain metastases in patients with non-small cell lung cancer.

Despite recent advances in technology, targeting, and chemotherapy, brain metastasis from non-small cell lung cancer (NSCLC) remains a significant problem. The vast majority of patients with this diagnosis undergo whole brain radiation therapy (WBRT). However, outcomes are still quite poor with median survivals measured in only months. In an effort to enhance outcomes from external beam radiation treatments, radiosensitizers have been investigated. Motexafin gadolinium (MGd) (Xcytrin, Sunnyvale, CA, USA) is a novel radiation sensitizer with a unique mechanism of action that may increase the th

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… Traditionally, boron neutron capture therapy has only modest efficacy in CNS tumors. This was largely because of a lack of tumor specificity to the boronated compounds. …

Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.

Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective aut

Partially reversible bortezomib-induced cardiotoxicity: an unusual cause of acute cardiomyopathy.

Chemotherapy-associated cardiotoxicity can present as a spectrum from arrhythmia to acute congestive heart failure. Unlike anthracyclines, proteasome inhibitors - for example, bortezomib - are not notorious for causing cardiotoxicity in absence of pre-existing cardiac dysfunction or without concomitant use of other cardiotoxic agents. We describe a 66-year-old woman with end-stage renal disease who developed acute dyspnea hours after a third treatment with bortezomib for IgG kappa myeloma. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) betwee

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… Bortezomib is a boron-containing molecule and proteasome inhibitor; the ubiquitin-proteasome system – the major pathway for intracellular protein degradation – plays a role in cell survival. Thus, proteasome inhibition induces cell apoptosis ( 3 ). …

H727 cells are inherently resistant to the proteasome inhibitor carfilzomib, yet require proteasome activity for cell survival and growth.

The second-in-class proteasome inhibitor (PI) carfilzomib (Kyprolis, Cfz) has contributed to a substantial advancement in multiple myeloma treatment by improving patient survival and quality of life. A considerable portion of patients however display intrinsic resistance to Cfz. Our mechanistic understanding of intrinsic Cfz resistance is limited due to a lack of suitable cell-based models. We report that H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). These

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… While the first-in-class PI drug Btz and the first oral PI Ixz utilize boronic acid pharmacophores, the second-generation PI Cfz harbors an epoxyketone that irreversibly inactivates the proteasome with high mechanistic selectivity 8 , 9 . … In order to examine this, we treated H727 cells with alternative PIs, particularly ones with differing pharmacophores or structures, such as Btz (a peptide boronic acid) and MG-132 (a peptide aldehyde). …

Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia.

Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clin

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… Bortezomib preferentially targets the β5 active site inside the 20S catalytic core of the proteasome; the boronic acid subgroup of bortezomib binds to the Thr1 residue on the β5 subunit, inhibiting the subunit’s chymotrypsin-like activity [ 32 , 38 , 116 ]. … Via hydrogen bonding, Gly47, Ala49/50, and Thr21 residues within the β5 subunit stabilize the interaction between Thr1 and the bortezomib’s boronic acid subgroup [ 116 ]. …

Роль антиоксидантов в множестве миеломы: диагностика, прогнозирование и терапевтическое применение: обзор сюжета.

Множественная миэлома (ММ) — злокачественная клетка B-клеток с моноклональными плазменными клетками, производящими нефункциональные иммуноглобулины. Она по-прежнему неизлечима из-за de novo или приобретенного сопротивления злокачественных клеток стандартным химиотерапиям. Таким образом, понимание механизма терапевтического сопротивления имеет важнейшее значение для разработки более эффективных мер вмешательства и определения новых целей лечения. MM - это разнородная болезнь, характеризующаяся сложными генетическими изменениями, которые имеют решающее значение для прогнозирования стратификации.

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… Interestingly, the inhibitory effect of vitamin C was restricted to PIs classes containing a peptide boronic acid, including BTZ and MG262. 91 Vitamin C abrogates the anticancer activity of BTZ through a direct binding between the hydroxyl group of vitamin C and the boronic acid of the BTZ. 113 Thus, … On the other hand, dietary or supplemental vitamin C can chemically neutralize boronate-based PI, such as BTZ, significantly reducing their therapeutic efficacy. …

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects.

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely

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… Bortezomib is a reversible boronic acid dipeptide which binds primarily the β5 subunit and, to a lesser extent, the β2 and β1 subunits of the catalytic 20S proteasome, blocking its chymotrypsin-like, trypsin-like and caspase-like activities, respectively [ 18 , 19 ]. … Crystal Structure of the Boronic Acid-Based Proteasome Inhibitor Bortezomib in Complex with the Yeast 20S Proteasome Structure 2006 14 451 456 10.1016/j.str.2005.11.019 16531229 20. Barrio S. Stühmer T. Da-Viá M. Barrio-Garcia C. Lehners N. Besse A. Cuenca I. Garitano-Trojaola A. Fink S. Leich E. …

The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells.

The proteasome inhibitors are a new class of antitumor agents. These inhibitors cause the accumulation of many proteins in the cell with the induction of apoptosis including TRAIL death receptors DR4 and DR5, but the role of the TRAIL apoptotic pathway in proteasome inhibitor cytotoxicity is unknown. Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5. In addition, FLICE-like

Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines.

Epstein-Barr virus (EBV) latent proteins exert anti-apoptotic effects on EBV-transformed lymphoid cells by down-regulating BCL2L11 (BIM), CDKN2A (p16(INK4A) ) and CDKN1A (p21(WAF1) ). However, the potential therapeutic effects of targeting these anti-apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp-restricted) and three lymphoblastoid cell lines (LCLs). We found that

Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting.

BACKGROUND: Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study h

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… peptidyl‐glutamyl peptidase, branched‐chain amino acid‐preferring, and small‐neutral amino acid‐preferring activities. 5 Several chemical compounds able to inhibit proteasome activity have been described including peptide analogues of substrates with different C‐terminal groups such as aldehydes, epoxyketones, boronic … experimental conditions such as sepsis, burn injury, cancer, immobilization, and denervation atrophy. 8 , 9 , 10 , 11 , 12 However, in recent years, bortezomib has attracted particular attention, as it was the first proteasome inhibitor approved for clinical use. 13 Bortezomib is a selective dipeptide boronic …

Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma.

Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾ 2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125-3.11 mg/m(2) on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1-36). MTD was determined to be 2.34 mg/m(2). Most common drug-related ad

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… inhibitor. 11 Like bortezomib, ixazomib binds to the β5 site of the 20S proteasome. 11 However, ixazomib has structural and physicochemical properties distinct from those of bortezomib, which may result in differences in activity and safety profiles. 11 Ixazomib (MLN2238) refers to the biologically active boronic … Under physiological conditions ixazomib citrate undergoes rapid hydrolysis to the biologically active boronic acid, ixazomib. 11 Ixazomib has shown improved preclinical activity compared with bortezomib in several lymphoma models, including a primary xenograft model derived from tissue of a bortezomib-refractory …