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1.
Artigo em Inglês | MEDLINE | ID: mdl-38768767

RESUMO

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

2.
Eur J Med Chem ; 261: 115790, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37690264

RESUMO

Dithiocarbamates (DTCs) are simple organic compounds with many applications in industry and medicine. They are potent metal chelators forming complexes with various metal ions, including copper. Recently, bis(diethyldithiocarbamate)-copper complex (CuET) has been identified as a metabolic product of the anti-alcoholic drug Antabuse (disulfiram, DSF), standing behind DSF's reported anticancer activity. Mechanistically, CuET in cells causes aggregation of NPL4 protein, an essential cofactor of the p97 segregase, an integral part of the ubiquitin-proteasome system. The malfunction of p97/NPL4 caused by CuET leads to proteotoxic stress accompanied by heat shock and unfolded protein responses and cancer cell death. However, it is not known whether the NPL4 inhibition is unique for CuET or whether it is shared with other dithiocarbamate-copper complexes. Thus, we tested 20 DTCs-copper complexes in this work for their ability to target and aggregate NPL4 protein. Surprisingly, we have found that certain potency against NPL4 is relatively common for structurally different DTCs-copper complexes, as thirteen compounds scored in the cellular NPL4 aggregation assay. These compounds also shared typical cellular phenotypes reported previously for CuET, including the NPL4/p97 proteins immobilization, accumulation of polyubiquitinated proteins, the unfolded protein, and the heat shock responses. Moreover, the active complexes were also toxic to cancer cells (the most potent in the nanomolar range), and we have found a strong positive correlation between NPL4 aggregation and cytotoxicity, confirming NPL4 as a relevant target. These results show the widespread potency of DTCs-copper complexes to target NPL4 with subsequent induction of lethal proteotoxic stress in cancer cells with implications for drug development.


Assuntos
Cobre , Neoplasias , Cobre/farmacologia , Proteínas/metabolismo , Dissulfiram/farmacologia , Ubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma , Neoplasias/tratamento farmacológico
3.
Cell Death Differ ; 30(7): 1666-1678, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37142656

RESUMO

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles.


Assuntos
Dissulfiram , Neoplasias , Animais , Humanos , Linhagem Celular Tumoral , Dissulfiram/metabolismo , Neoplasias/metabolismo , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/metabolismo
4.
Int J Mol Sci ; 24(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36769206

RESUMO

Cannabidiol (CBD) is an easily accessible and affordable Marijuana (Cannabis sativa L.) plant derivative with an extensive history of medical use spanning thousands of years. Interest in the therapeutic potential of CBD has increased in recent years, including its anti-tumour properties in various cancer models. In addition to the direct anticancer effects of CBD, preclinical research on numerous cannabinoids, including CBD, has highlighted their potential use in: (i) attenuating chemotherapy-induced adverse effects and (ii) enhancing the efficacy of some anticancer drugs. Therefore, CBD is gaining popularity as a supportive therapy during cancer treatment, often in combination with standard-of-care cancer chemotherapeutics. However, CBD is a biologically active substance that modulates various cellular targets, thereby possibly resulting in unpredictable outcomes, especially in combinations with other medications and therapeutic modalities. In this review, we summarize the current knowledge of CBD interactions with selected anticancer chemotherapeutics, discuss the emerging mechanistic basis for the observed biological effects, and highlight both the potential benefits and risks of such combined treatments. Apart from the experimental and preclinical results, we also indicate the planned or ongoing clinical trials aiming to evaluate the impact of CBD combinations in oncology. The results of these and future trials are essential to provide better guidance for oncologists to judge the benefit-versus-risk ratio of these exciting treatment strategies. We hope that our present overview of this rapidly advancing field of biomedicine will inspire more preclinical and clinical studies to further our understanding of the underlying biology and optimize the benefits for cancer patients.


Assuntos
Antineoplásicos , Canabidiol , Canabinoides , Cannabis , Neoplasias , Humanos , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Canabinoides/uso terapêutico , Interações Medicamentosas , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
5.
Cell Death Dis ; 13(3): 203, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35246527

RESUMO

Despite several approved therapeutic modalities, multiple myeloma (MM) remains an incurable blood malignancy and only a small fraction of patients achieves prolonged disease control. The common anti-MM treatment targets proteasome with specific inhibitors (PI). The resulting interference with protein degradation is particularly toxic to MM cells as they typically accumulate large amounts of toxic proteins. However, MM cells often acquire resistance to PIs through aberrant expression or mutations of proteasome subunits such as PSMB5, resulting in disease recurrence and further treatment failure. Here we propose CuET-a proteasome-like inhibitor agent that is spontaneously formed in-vivo and in-vitro from the approved alcohol-abuse drug disulfiram (DSF), as a readily available treatment effective against diverse resistant forms of MM. We show that CuET efficiently kills also resistant MM cells adapted to proliferate under exposure to common anti-myeloma drugs such as bortezomib and carfilzomib used as the first-line therapy, as well as to other experimental drugs targeting protein degradation upstream of the proteasome. Furthermore, CuET can overcome also the adaptation mechanism based on reduced proteasome load, another clinically relevant form of treatment resistance. Data obtained from experimental treatment-resistant cellular models of human MM are further corroborated using rather unique advanced cytotoxicity experiments on myeloma and normal blood cells obtained from fresh patient biopsies including newly diagnosed as well as relapsed and treatment-resistant MM. Overall our findings suggest that disulfiram repurposing particularly if combined with copper supplementation may offer a promising and readily available treatment option for patients suffering from relapsed and/or therapy-resistant multiple myeloma.


Assuntos
Antineoplásicos , Mieloma Múltiplo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Linhagem Celular Tumoral , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico
6.
Mol Oncol ; 16(7): 1541-1554, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34632694

RESUMO

Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies, case reports, and small clinical trials; however, ongoing clinical trials of advanced-stage cancer patients encounter variable results. Here, we show that one reason for the inconsistent clinical effects of DSF may reflect interference by other drugs. Using a high-throughput screening and automated microscopy, we identify cannabidiol, an abundant component of the marijuana plant used by cancer patients to mitigate side effects of chemotherapy, as a likely cause of resistance to DSF. Mechanistically, in cancer cells, cannabidiol triggers the expression of metallothioneins providing protective effects by binding heavy metal-based substances including the bis-diethyldithiocarbamate-copper complex (CuET). CuET is the documented anticancer metabolite of DSF, and we show here that the CuET's anticancer toxicity is effectively neutralized by metallothioneins. Overall, this work highlights an example of undesirable interference between cancer therapy and the concomitant usage of marijuana products. In contrast, we report that insufficiency of metallothioneins sensitizes cancer cells toward CuET, suggesting a potential predictive biomarker for DSF repurposing in oncology.


Assuntos
Canabidiol , Dissulfiram , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacologia , Dissulfiram/química , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Humanos , Metalotioneína
7.
Nat Commun ; 12(1): 713, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514738

RESUMO

Despite proteotoxic stress and heat shock being implicated in diverse pathologies, currently no methodology to inflict defined, subcellular thermal damage exists. Here, we present such a single-cell method compatible with laser-scanning microscopes, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin-proteasome system, providing unprecedented insights into the spatiotemporal response to thermal damage relevant for degenerative diseases, with broad applicability in biomedicine. Using this versatile method, we discover that HSP70 chaperone and its interactors are recruited to sites of thermally damaged proteins within seconds, and we report here mechanistically important determinants of such HSP70 recruitment. Finally, we demonstrate a so-far unsuspected involvement of p97(VCP) translocase in the processing of heat-damaged proteins. Overall, we report an approach to inflict targeted thermal protein damage and its application to elucidate cellular stress-response pathways that are emerging as promising therapeutic targets.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico , Análise de Célula Única/métodos , Proteína com Valosina/metabolismo , Linhagem Celular Tumoral , Temperatura Alta/efeitos adversos , Humanos , Nanopartículas Metálicas/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Prata/química , Ressonância de Plasmônio de Superfície , Ubiquitina/metabolismo , Proteína com Valosina/genética
8.
Cells ; 9(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085572

RESUMO

Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.


Assuntos
Dissuasores de Álcool/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Dano ao DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Dissulfiram/farmacologia , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Neoplasias/patologia , Proteínas Nucleares/metabolismo , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Proteína com Valosina/metabolismo
9.
Oncogene ; 38(40): 6711-6722, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31391554

RESUMO

Aldehyde dehydrogenase (ALDH) is a proposed biomarker and possible target to eradicate cancer stem cells. ALDH inhibition as a treatment approach is supported by anti-cancer effects of the alcohol-abuse drug disulfiram (DSF, Antabuse). Given that metabolic products of DSF, rather than DSF itself inhibit ALDH in vivo, and that DSF's anti-cancer activity is potentiated by copper led us to investigate the relevance of ALDH as the suggested molecular cancer-relevant target of DSF. Here we show that DSF does not directly inhibit ALDH activity in diverse human cell types, while DSF's in vivo metabolite, S-methyl-N,N-diethylthiocarbamate-sulfoxide inhibits ALDH activity yet does not impair cancer cell viability. Our data indicate that the anti-cancer activity of DSF does not involve ALDH inhibition, and rather reflects the impact of DSF's copper-containing metabolite (CuET), that forms spontaneously in vivo and in cell culture media, and kills cells through aggregation of NPL4, a subunit of the p97/VCP segregase. We also show that the CuET-mediated, rather than any ALDH-inhibitory activity of DSF underlies the preferential cytotoxicity of DSF towards BRCA1- and BRCA2-deficient cells. These findings provide evidence clarifying the confusing literature about the anti-cancer mechanism of DSF, a drug currently tested in clinical trials for repositioning in oncology.


Assuntos
Inibidores de Acetaldeído Desidrogenases/farmacologia , Aldeído Desidrogenase/antagonistas & inibidores , Antineoplásicos/farmacologia , Dissulfiram/farmacologia , Proteínas Nucleares/metabolismo , Células A549 , Inibidores de Acetaldeído Desidrogenases/metabolismo , Antineoplásicos/metabolismo , Meios de Cultura , Dissulfiram/metabolismo , Humanos , Células K562
10.
Prostate ; 79(4): 352-362, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30499118

RESUMO

BACKGROUND: Castration-resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically-supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol-abuse drug Antabuse) and its copper-chelating metabolite CuET that inhibit protein turnover. METHODS: Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio-resistant stem-cell like derived cells. Mechanistically, DNA damage repair, heat shock and unfolded protein response (UPR) pathways were assessed by immunofluorescence and immunoblotting. RESULTS: We observed enhanced sensitivity to PARPi/IR in PC3 cells consistent with lower homologous recombination (HR) repair. Vorinostat sensitized DU145 cells to PARPi/IR and decreased mutant p53. Vorinostat also impaired HR-mediated DNA repair, as determined by Rad51 foci formation and downregulation of TOPBP1 protein, and overcame radio-resistance of stem-cell like DU145-derived cells. All PCa models responded well to CuET or DSF combined with copper. We demonstrated that DSF interacts with copper in the culture media and forms adequate levels of CuET indicating that DSF/copper and CuET may be considered as comparable treatments. Both DSF/copper and CuET evoked hallmarks of UPR in PCa cells, documented by upregulation of ATF4, CHOP and phospho-eIF2α, with ensuing heat shock response encompassing activation of HSF1 and HSP70. Further enhancing the cytotoxicity of CuET, combination with an inhibitor of the anti-apoptotic protein survivin (YM155, currently undergoing clinical trials) promoted the UPR-induced toxicity, yielding synergistic effects of CuET and YM155. CONCLUSIONS: We propose that targeting genotoxic and proteotoxic stress responses by combinations of available drugs could inspire innovative strategies to treat castration-resistant PCa.


Assuntos
Dissulfiram/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Vorinostat/uso terapêutico , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Células PC-3 , PTEN Fosfo-Hidrolase/genética , Tolerância a Radiação , Reparo de DNA por Recombinação/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Proteína Supressora de Tumor p53/genética
11.
Nature ; 552(7684): 194-199, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29211715

RESUMO

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.


Assuntos
Dissuasores de Álcool , Alcoolismo/tratamento farmacológico , Antineoplásicos , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Adulto , Dissuasores de Álcool/farmacologia , Dissuasores de Álcool/uso terapêutico , Alcoolismo/epidemiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cobre/química , Dinamarca/epidemiologia , Dissulfiram/química , Feminino , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Proteínas Nucleares/química , Agregados Proteicos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos
12.
Crit Rev Oncol Hematol ; 92(2): 61-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24890785

RESUMO

Since their introduction to the clinic 10 years ago, proteasome inhibitors have become the cornerstone of anti-multiple myeloma therapy. Despite significant progress in understanding the consequences of proteasome inhibition, the unique activity of bortezomib is still unclear. Disappointing results from clinical trials with bortezomib in other malignancies raise the question of what makes multiple myeloma so sensitive to proteasome inhibition. Successful administration of bortezomib in various immunological disorders that exhibit high antibody production suggests that the balance between protein synthesis and degradation is a key determinant of sensitivity to proteasome inhibition because a high rate of protein production is a shared characteristic in plasma and myeloma cells. Initial or acquired resistance to bortezomib remains a major obstacle in the clinic as in vitro data from cell lines suggest a key role for the ß5 subunit mutation in resistance; however the mutation was not found in patient samples. Recent studies indicate the importance of selecting for a subpopulation of cells that produce lower amounts of paraprotein during bortezomib therapy.


Assuntos
Antineoplásicos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Ácidos Borônicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Pirazinas/uso terapêutico , Animais , Doenças Autoimunes/metabolismo , Bortezomib , Humanos , Mieloma Múltiplo/metabolismo
13.
Mini Rev Med Chem ; 12(12): 1184-92, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22931589

RESUMO

The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.


Assuntos
Complexos de Coordenação/química , Cobre/química , Ditiocarb/química , Inibidores de Proteassoma/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Ácidos Borônicos/uso terapêutico , Bortezomib , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Humanos , Estresse Oxidativo/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Pirazinas/química , Pirazinas/farmacologia , Pirazinas/uso terapêutico
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