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1.
J Exp Clin Cancer Res ; 38(1): 453, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694672

RESUMO

BACKGROUND: The first line therapy for patients with diffuse large B cell (DLBCL) is R-CHOP. About half of DLBCL patients are either refractory to, or will relapse, after the treatment. Therefore, identifying novel drug targets and effective therapeutic agents is urgently needed for improving DLBCL patient survival. b-AP15, a selective small molecule inhibitor of proteasomal USP14 and UCHL5 deubiquitinases (DUBs), has shown selectivity and efficacy in several other types of cancer cells. This is the first study to report the effect of b-AP15 in DLBCL. METHODS: Cell lines of two DLBCL subtypes, Germinal Center B Cell/ GCB (SU-DHL-4, OCI-LY-1, OCI-LY-19) and Activated B Cell/ABC (SU-DHL-2), were used in the current study. Cell viability was measured by MTS assay, proliferation by trypan blue exclusion staining assay, cellular apoptosis by Annexin V-FITC/PI staining and mitochondrial outer membrane permeability assays, the activities of 20S proteasome peptidases by cleavage of specific fluorogenic substrates, and cell migration was detected by transwell assay in these GCB- and ABC-DLBCL cell lines. Mouse xenograft models of SU-DHL-4 and SU-DHL-2 cells were used to determine in vivo effects of b-AP15 in DLBCL tumors. RESULTS: b-AP15 inhibited proteasome DUB activities and activated cell death pathway, as evident by caspase activation and mitochondria apoptosis in GCB- and ABC- DLBCL cell lines. b-AP15 treatment suppressed migration of GCB- and ABC-DLBCL cells via inhibiting Wnt/ß-catenin and TGFß/Smad pathways. Additionally, b-AP15 significantly inhibited the growth of GCB- and ABC DLBCL in xenograft models. CONCLUSIONS: These results indicate that b-AP15 inhibits cell migration and induces apoptosis in GCB- and ABC-DLBCL cells, and suggest that inhibition of 19S proteasomal DUB should be a novel strategy for DLBCL treatment.

2.
Cancer Lett ; 465: 118-128, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31518603

RESUMO

Breast cancer is the most common malignancy in women around the world. Estrogen receptor α (ERα) is expressed in approximately 70% of breast tumors, and considered as one of most effective targets in breast cancer therapy. It has been reported that the degradation of ERα protein is mediated by ubiquitin-proteasome system. However, little is known about the regulation of ERα deubiquitination, a critical constituent of its degradation control. The current study first reports that there is a positive correlation between ERα and ubiquitin specific protease 7 (USP7) protein levels in human breast tumor tissues. Subsequent studies showed that USP7 physically interacted with the ERα, thereby mediating the deubiquitination and stabilization of ERα. In addition, USP7 inhibition or silencing led to growth inhibition and apoptosis of ERα-positive breast cancer cells both in vitro and in vivo. Furthermore, overexpression of ERα rescued the USP7 silencing-induced cell cycle arrest and apoptosis, supporting that ERα status is essential to the function of USP7 in breast carcinogenesis. Overall, this study suggests that targeting USP7-ERα complex could be a potential strategy to treat ERα-positive breast cancer.

3.
Curr Pharm Des ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419930

RESUMO

Repurposing already approved drugs as new anticancer agents is a promising strategy since the advantages of low costs, low risks and time-saving. Disulfiram (DSF), as the first drug for anti-alcoholism, was approved by the U.S. Food and Drug Administration (FDA) over 60 years ago. Increasing evidence indicates that DSF has a great potential for the treatment of various human cancers. Several mechanisms and targets of DSF related to cancer therapy have been proposed, including inhibition of ubiquitin-proteasome system (UPS), cancer cell stemness and cancer metastasis, and alteration of the intracellular reactive oxygen species (ROS). This article provides a brief review of the history of DSF's use in humans and its molecular mechanisms and targets in anticancer therapy, describes DSF delivery strategies for cancer treatment, summarizes completed and ongoing cancer clinical trials involving DSF, and offers strategies to better use DSF in cancer therapies.

4.
Nutrients ; 11(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027187

RESUMO

Tea, including green tea made from the leaves of the Camellia senenisis plant, is the second most consumed beverage worldwide after water, and is consumed by more than two-thirds of the world population [...].

5.
J Cell Biochem ; 120(8): 14065-14075, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30963630

RESUMO

The levels of organic pollutants, such as optical brightener (OB) compounds, in the global environment have been increasing in recent years. The toxicological effects and signal transduction systems associated with OB toxicity have not been thoroughly studied. The ubiquitin-proteasome system (UPS) plays a crucial role in regulating multiple essential cellular processes, and proteasome-associated cysteine deubiquitinases (DUBs), ubiquitin C-terminal hydrolase L5 (UCHL5) and USP14, are two major regulators for (de)ubiquitination and stability of many important target proteins. Therefore, potential inhibition of UCHL5 and USP14 activities by some environmental chemicals might cause in vivo toxicity. In the current study we hypothesize that electrophilic OB compounds, such as 4,4'-diamino-2,2'-stilbenedisulfonic acid(DAST), fluorescent brightener 28 (FB-28) and FB-71, can interact with the catalytic triads (CYS, HIS, and ASP) of UCHL5 and USP14 and inhibit their enzymatic activities, leading to cell growth suppression. This hypothesis is supported by our findings presented in this study. Results from in silico computational docking and ubiquitin vinyl sulfone assay confirmed the UCHL5/USP14-inhibitory activities of these OB compounds that have potencies in an order of: FB-71 > FB-28 > DAST. Furthermore, inhibition of these two proteasomal DUBs by OBs resulted in cell growth inhibition and apoptosis induction in two human breast cancer cell models. In addition, we found that OB-mediated DUB inhibition triggers a feedback reaction in which expression of UCHL5 and USP14 proteins is increased to compromise the suppressed activities. Our study suggests that these commonly used OB compounds may target and inhibit proteasomal cysteine DUBs, which should contribute to their toxicological effects in vivo.

7.
Sci Rep ; 9(1): 236, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659204

RESUMO

Tumor initiating cells (TIC) have been suggested as a mechanism for driving chemoresistance and tumor recurrence in human cancers including triple negative breast cancer (TNBC). Significant progress has been made in targeting TICs. However, methods for simultaneously targeting heterogeneous TIC populations are lacking. In this study, we found that treating TNBC cells with chemotherapeutic agents led to a significant accumulation of the ALDH+ TIC population. Treating TNBC cells with a disulfiram and copper mixture (DSF/Cu) specifically decreased the ALDH+ TIC population and treatment with BKM120, a pan-PI3K inhibitor, significantly decreased the CD44+/CD24- TIC population. Furthermore, treatment with DSF/Cu or BKM120 induced higher levels of apoptosis in ALDH+ or CD44+/CD24- populations, respectively, than in bulk tumor cells. Combining DSF/Cu and BKM120 treatment simultaneously decreased the ALDH+ and CD44+/CD24- TICs. Using a TNBC tumor xenograft mouse model, we found that DSF/BKM in combination with Taxol significantly reduced the tumor burden and delayed tumor recurrence compared to Taxol treatment alone. Our study is the first of its kind to use two different drugs to abolish two major TIC subtypes simultaneously and inhibit tumor recurrence. These results lay a foundation for developing a novel therapy that can improve chemotherapeutic efficacy.

8.
Nutrients ; 10(11)2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30400270

RESUMO

The 5'-3' structure-specific endonuclease ERCC1/XPF (Excision Repair Cross-Complementation Group 1/Xeroderma Pigmentosum group F) plays critical roles in the repair of cisplatin-induced DNA damage. As such, it has been identified as a potential pharmacological target for enhancing clinical response to platinum-based chemotherapy. The goal of this study was to follow up on our previous identification of the compound NSC143099 as a potent inhibitor of ERCC1/XPF activity by performing an in silico screen to identify structural analogues that could inhibit ERCC1/XPF activity in vitro and in vivo. Using a fluorescence-based DNA-endonuclease incision assay, we identified the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as a potent inhibitor of ERCC1/XPF activity with an IC50 (half maximal inhibitory concentration) in the nanomolar range in biochemical assays. Using DNA repair assays and clonogenic survival assays, we show that EGCG can inhibit DNA repair and enhance cisplatin sensitivity in human cancer cells. Finally, we show that a prodrug of EGCG, Pro-EGCG (EGCG octaacetate), can enhance response to platinum-based chemotherapy in vivo. Together these data support a novel target of EGCG in cancer cells, namely ERCC1/XPF. Our studies also corroborate previous observations that EGCG enhances sensitivity to cisplatin in multiple cancer types. Thus, EGCG or its prodrug makes an ideal candidate for further pharmacological development with the goal of enhancing cisplatin response in human tumors.

9.
Expert Opin Ther Pat ; 28(12): 919-937, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30449221

RESUMO

INTRODUCTION: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs. Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators. Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3-substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs.

10.
J Cell Biochem ; 119(11): 9006-9016, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30015387

RESUMO

Isothiocyanates (ITCs) are natural chemoprotective products found abundantly in cruciferous vegetables. However, the cancer-relevant targets and molecular mechanisms of ITCs remain unclear. We hypothesize that ITCs, as electrophiles, can interact with the catalytic triads (CYS, HIS, and ASP) of the proteasomal cysteine deubiquitinases USP14 and UCHL5, ultimately inhibiting their activities. In the current study, we exploited this possibility by performing both computational docking and biochemical validation assays using human breast and prostate cancer cell models. Docking results suggest that benzyl isothiocyanate, phenethyl isothiocyanate, and DL-sulforaphane are more potent inhibitors of UCHL5 than USP14, and these ITCs could interact with the catalytic triads of UCHL5 and USP14. Indeed, ubiquitin vinyl sulfone assay confirmed the inhibitory activity of each ITC on the ubiquitin-binding activity of UCHL5 and USP14. We also found that inhibition of USP-14 and UCHL5 activities by the ITCs caused increased levels of USP14 and UCHL5 proteins, but not the third 19S-deubiquitinating enzyme (DUB), POH1/RPN11, suggesting feedback loop activation and further supporting that ITCs are inhibitors of proteasomal cysteine DUBs. Associated with DUB inhibition by ITCs, ubiquitinated proteins were significantly increased, accompanied with induction of apoptosis, inhibition of proliferation and suppression of cell invasion. Our findings of ITCs as proteasomal cysteine DUB inhibitors should provide insightful information for designing, discovering and developing potent, specific 19S-DUB inhibitors for cancer therapies.

11.
Eur J Med Chem ; 155: 418-427, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29906688

RESUMO

Basal like breast cancer (BLBC) is a very aggressive subtype of breast cancer giving few chances of survival, against which cisplatin based therapy is a compromise among the anticancer activity, the resistance development and the severe side effects. With the aim of finding new anticancer agents alternative to cisplatin, seven gold(I) azolate/phosphane compounds were evaluated in vitro by MTT tests in human MDA-MB-231, human mammary epithelial HMLE cells overexpressing FoxQ1, and murine A17 cells as models of BLBC. Two compounds, (4,5-dichloro-1H-imidazolate-1-yl)-(triphenylphosphane)-gold(I) 1 and (4,5-dicyano-1H-imidazolate-1-yl)-(triphenylphosphane)-gold(I) 2 were found very active and chosen for an in vivo study in A17 tumors transplanted in syngeneic mice. The compounds resulted to be more active than cisplatin, less nephrotoxic and generally more tolerated by the mice. This study also provides evidence that both gold(I) complexes inhibited the 19 S proteasome-associated deubiquitinase USP14 and induced apoptosis, while compound 1's mechanism of action depends also on its ability to down-regulate key molecules governing cancer growth and progression, such as STAT3 and Cox-2.


Assuntos
Antineoplásicos/farmacologia , Azóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Fosfinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/química , Fosfinas/química , Relação Estrutura-Atividade
12.
J Trace Elem Med Biol ; 48: 233-238, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29773186

RESUMO

Cadmium is a known carcinogen that has been implicated in prostate cancer, but how it affects prostate carcinogenesis in humans remains unclear. Evidence from basic science suggests that cadmium can bind to the androgen receptor causing endocrine disruption. The androgen receptor is required for normal prostate development and is the key driver of prostate cancer progression. In this study, we examined the association between cadmium content and androgen receptor protein expression in prostate cancer tissue of African American (N = 22) and European American (N = 30) men. Although neither overall tumor cadmium content (log transformed) nor androgen receptor protein expression level differed by race, we observed a race-cadmium interaction with regard to androgen receptor expression (P = 0.003) even after accounting for age at prostatectomy, smoking history, and Gleason score. African American men had a significant positive correlation between tumor tissue cadmium content and androgen receptor expression (Pearson correlation = 0.52, P = 0.013), while European Americans showed a non-significant negative correlation between the two (Pearson correlation = -0.19, P = 0.31). These results were unchanged after further accounting for tissue zinc content or dietary zinc or selenium intake. African American cases with high-cadmium content (>median) in tumor tissue had more than double the androgen receptor expression (0.021 vs. 0.008, P = 0.014) of African American men with low-cadmium level. No difference in androgen receptor expression was observed in European Americans by cadmium level (high 0.015 vs. low 0.011, P = 0.30). Larger studies are needed to confirm these results and if upheld, determine the biologic mechanism by which cadmium increases androgen receptor protein expression in a race-dependent manner. Our results suggest that cadmium may play a role in race disparities observed in prostate cancer.


Assuntos
Cádmio/análise , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Afro-Americanos , Grupo com Ancestrais do Continente Europeu , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
13.
Expert Opin Drug Discov ; 13(7): 643-660, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29688074

RESUMO

INTRODUCTION: Increasing evidence has expanded the role of green tea from a traditional beverage to a source of pharmacologically active molecules with diverse health benefits. However, conclusive clinical results are needed to better elucidate the cancer-preventive and therapeutic effects of green tea polyphenols (GTPs). Areas covered: The authors describe GTPs' chemical compositions and metabolic biotransformations, and their recent developments in drug discovery, focusing on their cancer chemopreventive and therapeutic effects. They then review the recent development of GTP-loaded nanoparticles and GTP prodrugs. Expert opinion: GTPs possess potent anticarcinogenic activities through interfering with the initiation, development and progression phases of cancer. There are several challenges (e.g. poor bioavailability) in developing GTPs as therapeutic agents. Use of nanoparticle-based delivery systems has provided unique advantages over purified GTPs. However, there is still a need to determine the actual magnitude and pharmacological mechanisms of GTPs encapsulated in nanoparticles, in order to address newly emerging safety issues associated with the potential 'local overdose' effect. The use of Pro- epigallocatechin gallate (Pro-EGCG) as a prodrug appears to offer improved in vitro stability as well as better in vivo bioavailability and efficacies in a number of animal studies, suggesting its potential as a therapeutic agent for further study and development.

14.
Oncogene ; 37(14): 1896-1910, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29353883

RESUMO

It has been well known that androgen receptor (AR) is critical to prostate cancer development and progression. It has also been documented that AR is expressed in more than 60% of breast tumors, which promotes the growth of estrogen receptor-negative (ER-)/AR-positive (AR+) breast cancer cells. Thus, AR might be a potential therapeutic target for AR-positive/ER-negative breast cancer patients. Previously we reported that in prostate cancer cells proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) stabilized AR protein level by removing its ubiquitin chain. In the current study, we studied the USP14-AR protein interaction and cell proliferation status after USP14 reduction or inhibition in breast cancer cells, and our results support the conclusion that targeting USP14 is a novel strategy for treating AR-responsive breast cancer. We found that inhibition of USP14 accelerated the K48-ubiquitination and proteasome-mediated degradation of AR protein. Additionally, both genetic and pharmacological inhibition of USP14 significantly suppressed cell proliferation in AR-responsive breast cancer cells by blocking G0/G1 to S phase transition and inducing apoptosis. Moreover, AR overexpression inhibited USP14 inhibition-induced events, suggesting that AR deubiquitination by USP14 is critical for breast cancer growth and USP14 inhibition is a possible strategy to treat AR-positive breast cancer.

15.
Curr Med Chem ; 25(4): 506-524, 2018 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-29065820

RESUMO

BACKGROUND: Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how their metal-binding ability is related to their anticancer activity. This review aims to summarize chemical features and metal-binding activity of disulfiram and its metabolite DEDTC, and discuss different mechanisms of action of disulfiram and their contributions to the drug's anticancer activity. METHODS: We undertook a disulfiram-related search on bibliographic databases of peerreviewed research literature, including many historic papers and in vitro, in vivo, preclinical and clinical studies. The selected papers were carefully reviewed and summarized. RESULTS: More than five hundreds of papers were obtained in the initial search and one hundred eighteen (118) papers were included in the review, most of which deal with chemical and biological aspects of Disulfiram and the relationship of its chemical and biological properties. Eighty one (81) papers outline biological aspects of dithiocarbamates, and fifty seven (57) papers report biological activity of Disulfiram as an inhibitor of proteasomes or inhibitor of aldehyde dehydrogenase enzymes, interaction with other anticancer drugs, or mechanism of action related to reactive oxygen species. Other papers reviewed focus on chemical aspects of dithiocarbamates. CONCLUSION: This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Dissulfiram/química , Dissulfiram/farmacologia , Metais/química , Inibidores de Acetaldeído Desidrogenases/química , Inibidores de Acetaldeído Desidrogenases/farmacologia , Reposicionamento de Medicamentos , Humanos , Neoplasias/tratamento farmacológico
16.
Curr Protein Pept Sci ; 19(4): 358-367, 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-28079010

RESUMO

Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged by success of bortezomib in the treatment of multiple myeloma, several second-generation proteasome inhibitors have been developed based on natural resources, and are being tested in various clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including their natural product origins, compound-discovery and optimization, as well as their current status in both preclinical and clinical studies.

17.
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
18.
Cancer Metastasis Rev ; 36(4): 717-736, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29047025

RESUMO

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Ubiquitina/antagonistas & inibidores , Animais , Reposicionamento de Medicamentos , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Ubiquitina/metabolismo
19.
Cancer Metastasis Rev ; 36(4): 559-560, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29039080
20.
Cancer Metastasis Rev ; 36(4): 655-668, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29039082

RESUMO

Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs. The successful clinical application of cisplatin in cancer treatment has prompted researchers to develop various metal-based anticancer agents with new properties. Recently, we have reported that several metal-based drugs, such as the antirheumatic gold agent auranofin (AF), the antifouling paint biocides copper pyrithione (CuPT) and zinc pyrithione (ZnPT), and also our two synthesized complexes platinum pyrithione (PtPT) and nickel pyrithione (NiPT), can target the proteasomal DUBs UCHL5 and USP14. In this review, we summarize the recently reported small molecule inhibitors of proteasomal DUBs, with a focus on discussion of the unique nature of metal-based proteasomal DUB inhibitors and their anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Enzimas Desubiquitinantes/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Compostos Organometálicos/farmacologia , Inibidores de Proteassoma/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Enzimas Desubiquitinantes/metabolismo , Humanos
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