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1.
Mol Cancer ; 23(1): 120, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38831402

RESUMO

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.


Assuntos
Aclarubicina , Antraciclinas , Leucemia Mieloide Aguda , Animais , Feminino , Humanos , Masculino , Aclarubicina/farmacologia , Aclarubicina/uso terapêutico , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Resultado do Tratamento
2.
Small ; 20(8): e2306334, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37817372

RESUMO

While a multitude of studies have appeared touting the use of molecules as electronic components, the design of molecular switches is crucial for the next steps in molecular electronics. In this work, single-molecule devices incorporating spiropyrans, made using break junction techniques, are described. Linear spiropyrans with electrode-contacting groups linked by alkynyl spacers to both the indoline and chromenone moieties have previously provided very low conductance values, and removing the alkynyl spacer has resulted in a total loss of conductance. An orthogonal T-shaped approach to single-molecule junctions incorporating spiropyran moieties in which the conducting pathway lies orthogonal to the molecule backbone is described and characterized. This approach has provided singlemolecule conductance features with good correlation to molecular length. Additional higher conducting states are accessible using switching induced by UV light or protonation. Theoretical modeling demonstrates that upon (photo)chemical isomerization to the merocyanine, two cooperating phenomena increase conductance: release of steric hindrance allows the conductance pathway to become more planar (raising the mid-bandgap transmission) and a bound state introduces sharp interference near the Fermi level of the electrodes similarly responding to the change in state. This design step paves the way for future use of spiropyrans in single-molecule devices and electrosteric switches.

3.
Cancer Discov ; 13(10): 2212-2227, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37548431

RESUMO

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in treatment-naive head and neck squamous cell carcinoma, we analyzed primary tumor immune infiltrates from responding and nonresponding patients. At baseline, a higher ratio between active (4-1BB/OX40+) and inactive regulatory CD4+ T cells was associated with immunotherapy response. Furthermore, upon therapy, this active regulatory T-cell (Treg) population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells displayed decreased expression of activity and dysfunction-related genes in responding patients, whereas in clinical nonresponders, natural killer cells showed an increased cytotoxic profile early upon treatment. These data reveal immunologic changes in response to dual PD-1/CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive Treg and CD8+ T-cell compartments in responding patients, and indicate that the presence of activated Tregs at baseline may be associated with response. SIGNIFICANCE: In head and neck squamous cell carcinoma, neoadjuvant PD-1/CTLA4 blockade has shown substantial response rates (20%-35%). As recognition of tumor antigens by T cells appears to be a critical driver of therapy response, a better understanding of alterations in T-cell state that are associated with response and resistance is of importance. This article is featured in Selected Articles from This Issue, p. 2109.

4.
J Phys Chem C Nanomater Interfaces ; 127(26): 12802-12810, 2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37435408

RESUMO

The environment surrounding a molecular junction affects its charge-transport properties and, therefore, must be chosen with care. In the case of measurements in liquid media, the solvent must provide good solvation, grant junction stability, and, in the case of electrolyte gating experiments, allow efficient electrical coupling to the gate electrodes through control of the electrical double layer. We evaluated in this study the deep eutectic solvent mixture (DES) ethaline, which is a mixture of choline chloride and ethylene glycol (1:2), for single-molecule junction fabrication with break-junction techniques. In ethaline, we were able to (i) measure challenging and poorly soluble molecular wires, exploiting the improved solvation capabilities offered by DESs, and (ii) efficiently apply an electrostatic gate able to modulate the conductance of the junction by approximately an order of magnitude within a ∼1 V potential window. The electrochemical gating results on a Au-VDP-Au junction follow exceptionally well the single-level modeling with strong gate coupling (where VDP is 1,2-di(pyridine-4-yl)ethene). Ethaline is also an ideal solvent for the measurement of very short molecular junctions, as it grants a greatly reduced snapback distance of the metallic electrodes upon point-contact rupture. Our work demonstrates that DESs are viable alternatives to often relatively expensive ionic liquids, offering good versatility for single-molecule electrical measurements.

5.
Angew Chem Int Ed Engl ; 61(23): e202116985, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35289977

RESUMO

Integrating radical (open-shell) species into non-cryogenic nanodevices is key to unlocking the potential of molecular electronics. While many efforts have been devoted to this issue, in the absence of a chemical/electrochemical potential the open-shell character is generally lost in contact with the metallic electrodes. Herein, single-molecule devices incorporating a 6-oxo-verdazyl persistent radical have been fabricated using break-junction techniques. The open-shell character is retained at room temperature, and electrochemical gating permits in situ reduction to a closed-shell anionic state in a single-molecule transistor configuration. Furthermore, electronically driven rectification arises from bias-dependent alignment of the open-shell resonances. The integration of radical character, transistor-like switching, and rectification in a single molecular component paves the way to further studies of the electronic, magnetic, and thermoelectric properties of open-shell species.

6.
Nat Commun ; 12(1): 7348, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34937871

RESUMO

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Imunoterapia , Ipilimumab/uso terapêutico , Terapia Neoadjuvante , Nivolumabe/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Fluordesoxiglucose F18/química , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Sequenciamento do Exoma
7.
Genome Med ; 13(1): 166, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663432

RESUMO

BACKGROUND: Liver cancer is one of the most commonly diagnosed cancers and the fourth leading cause of cancer-related death worldwide. Broad-spectrum kinase inhibitors like sorafenib and lenvatinib provide only modest survival benefit to patients with hepatocellular carcinoma (HCC). This study aims to identify novel therapeutic strategies for HCC patients. METHODS: Integrated bioinformatics analyses and a non-biased CRISPR loss of function genetic screen were performed to identify potential therapeutic targets for HCC cells. Whole-transcriptome sequencing (RNA-Seq) and time-lapse live imaging were performed to explore the mechanisms of the synergy between CDC7 inhibition and ATR or CHK1 inhibitors in HCC cells. Multiple in vitro and in vivo assays were used to validate the synergistic effects. RESULTS: Through integrated bioinformatics analyses using the Cancer Dependency Map and the TCGA database, we identified ATR-CHK1 signaling as a therapeutic target for liver cancer. Pharmacological inhibition of ATR or CHK1 leads to robust proliferation inhibition in liver cancer cells having a high basal level of replication stress. For liver cancer cells that are resistant to ATR or CHK1 inhibition, treatment with CDC7 inhibitors induces strong DNA replication stress and consequently such drugs show striking synergy with ATR or CHK1 inhibitors. The synergy between ATR-CHK1 inhibition and CDC7 inhibition probably derives from abnormalities in mitosis inducing mitotic catastrophe. CONCLUSIONS: Our data highlights the potential of targeting ATR-CHK1 signaling, either alone or in combination with CDC7 inhibition, for the treatment of liver cancer.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Quinase 1 do Ponto de Checagem/genética , Replicação do DNA , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Animais , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nanoscale Adv ; 3(11): 3136-3144, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-34124578

RESUMO

Selective unidirectional transport of barium ions between droplets in a water-in-chloroform emulsion is demonstrated. Gold nanoparticles (GNPs) modified with a thiolated crown ether act as barium ion complexing shuttles that carry the ions from one population of droplets (source) to another (target). This process is driven by a steep barium ion concentration gradient between source and target droplets. The concentration of barium ions in the target droplets is kept low at all times by the precipitation of insoluble barium sulfate. A potential role of electrostatically coupled secondary processes that maintain the electroneutrality of the emulsion droplets is discussed. Charging of the GNP metal cores by electron transfer in the presence of the Fe(ii)/Fe(iii) redox couple appears to affect the partitioning of the GNPs between the water droplets and the chloroform phase. Processes have been monitored and studied by optical microscopy, Raman spectroscopy, cryogenic scanning electron microscopy (cryo-SEM) and zeta potential. The shuttle action of the GNPs has further been demonstrated electrochemically in a model system.

9.
FEBS J ; 288(21): 6095-6111, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33022843

RESUMO

The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.


Assuntos
Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Aclarubicina/toxicidade , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos
10.
Proc Natl Acad Sci U S A ; 117(26): 15182-15192, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554494

RESUMO

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.


Assuntos
Antineoplásicos/efeitos adversos , Cromatina/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Animais , Linhagem Celular , Doxorrubicina/análogos & derivados , Doxorrubicina/síntese química , Doxorrubicina/metabolismo , Doxorrubicina/uso terapêutico , Cardiopatias/induzido quimicamente , Histonas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos
11.
Angew Chem Int Ed Engl ; 59(29): 12029-12034, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32271489

RESUMO

Polyoxometalates have been proposed in the literature as nanoelectronic components, where they could offer key advantages with their structural versatility and rich electrochemistry. Apart from a few studies on their ensemble behaviour (as monolayers or thin films), this potential remains largely unexplored. We synthesised a pyridyl-capped Anderson-Evans polyoxometalate and used it to fabricate single-molecule junctions, using the organic termini to chemically "solder" a single cluster to two nanoelectrodes. Operating the device in an electrochemical environment allowed us to probe charge transport through different oxidation states of the polyoxometalate, and we report here an efficient three-state transistor behaviour. Conductance data fits a quantum tunnelling mechanism with different charge-transport probabilities through different charge states. Our results show the promise of polyoxometalates in nanoelectronics and give an insight on their single-entity electrochemical behaviour.

12.
Am J Hematol ; 94(1): 93-102, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30370942

RESUMO

Adult B-lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre-existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)-anchor deficient CD52-negative B-cell populations are frequently present already at diagnosis in B-ALL patients, but not in patients suffering from other B-cell malignancies. We demonstrate that the GPI-anchor negative phenotype results from loss of mRNA expression of the PIGH gene, which is involved in the first step of GPI-anchor synthesis. Loss of PIGH mRNA expression within these B-ALL cells follows epigenetic silencing rather than gene mutation or deletion. The coinciding loss of CD52 membrane expression may contribute to the development of resistance to alemtuzumab (ALM) treatment in B-ALL patients resulting in the outgrowth of CD52-negative escape variants. Additional treatment with 5-aza-2'-deoxycytidine may restore expression of CD52 and revert ALM resistance.


Assuntos
Linfócitos B/metabolismo , Antígeno CD52/deficiência , Metilação de DNA/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica , Inativação Gênica , Glicosilfosfatidilinositóis/deficiência , Proteínas de Membrana/genética , Proteínas de Neoplasias/deficiência , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Alemtuzumab/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/patologia , Antígeno CD52/biossíntese , Antígeno CD52/genética , Linhagem Celular Tumoral , Decitabina/farmacologia , Decitabina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Glicosilfosfatidilinositóis/biossíntese , Glicosilfosfatidilinositóis/genética , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
13.
Oncotarget ; 8(43): 73925-73937, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-29088757

RESUMO

Treatment of advanced head and neck squamous cell carcinoma (HNSCC) is plagued by low survival and high recurrence rates, despite multimodal therapies. Presently, cisplatin or cetuximab is used in combination with radiotherapy which has resulted in minor survival benefits but increased severe toxicities relative to RT alone. This underscores the urgent need for improved tumor-specific radiosensitizers for better control with lower toxicities. In a small molecule screen targeting kinases, performed on three HNSCC cell lines, we identified GSK635416A as a novel radiosensitizer. The extent of radiosensitization by GSK635416A outperformed the radiosensitization observed with cisplatin and cetuximab in our models, while exhibiting virtually no cytotoxicity in the absence of radiation and in normal fibroblast cells. Radiation induced phosphorylation of ATM was inhibited by GSK635416A. GSK63541A increased DNA double strand breaks after radiation and GSK63541A mediated radiosensitization was lacking in ATM-mutated cells thereby further supporting the ATM inhibiting properties of GSK63541A. As a novel ATM inhibitor with highly selective radiosensitizing activity, GSK635416A holds promise as a lead in the development of drugs active in potentiating radiotherapy for HNSCC and other cancer types.

14.
Cancer Res ; 75(19): 4176-87, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26260527

RESUMO

The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase IIα, respectively, whereas deletion of C9orf82 augments subsequent DSB repair. Their corresponding genes, frequently mutated or deleted in human tumors, may impact drug sensitivity, as exemplified by triple-negative breast cancer patients with diminished SWI/SNF core member expression who exhibit reduced responsiveness to chemotherapy regimens containing doxorubicin. Collectively, our work identifies genes that may predict the response of cancer patients to the broadly used topoisomerase II poisons and defines alternative pathways that could be therapeutically exploited in treatment-resistant patients.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Proteínas Cromossômicas não Histona/fisiologia , Proteínas de Ligação a DNA/fisiologia , Resistencia a Medicamentos Antineoplásicos/genética , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Nucleares/fisiologia , Inibidores da Topoisomerase II/farmacologia , Fatores de Transcrição/fisiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/genética , Sistemas CRISPR-Cas , Capecitabina/administração & dosagem , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/metabolismo , Proteínas Cromossômicas não Histona/genética , Ciclofosfamida/administração & dosagem , DNA Helicases/análise , Proteínas de Ligação a DNA/genética , Docetaxel , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Etoposídeo/farmacologia , Feminino , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Proteínas de Neoplasias/análise , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Proteína SMARCB1 , Sarcoma/metabolismo , Sarcoma/patologia , Taxoides/administração & dosagem , Topotecan/farmacologia , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
15.
Nat Chem Biol ; 11(7): 472-80, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25961671

RESUMO

Many anticancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors additionally cause histone eviction. Here, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. The TopoI inhibitor topotecan and the TopoII inhibitor etoposide are similar in inducing DNA damage at transcriptionally active genomic regions. The anthracycline daunorubicin induces DNA breaks and evicts histones from active chromatin, thus quenching local DNA damage responses. Another anthracycline, aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.


Assuntos
Antineoplásicos/farmacologia , DNA de Neoplasias/química , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Aclarubicina/química , Aclarubicina/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Cromatina/química , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Dano ao DNA , DNA de Neoplasias/metabolismo , Daunorrubicina/química , Daunorrubicina/farmacologia , Etoposídeo/química , Etoposídeo/farmacologia , Histonas/antagonistas & inibidores , Histonas/química , Histonas/genética , Histonas/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/química , Neoplasias/genética , Neoplasias/patologia , Especificidade de Órgãos , Transporte Proteico/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Topotecan/química , Topotecan/farmacologia
16.
Nat Commun ; 4: 1908, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23715267

RESUMO

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.


Assuntos
Cromatina/química , Cromatina/metabolismo , Doxorrubicina/farmacologia , Histonas/metabolismo , Conformação de Ácido Nucleico , Aclarubicina/química , Aclarubicina/farmacologia , Animais , Antraciclinas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Crise Blástica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Dano ao DNA , Doxorrubicina/química , Etoposídeo/química , Etoposídeo/farmacologia , Coração/efeitos dos fármacos , Humanos , Substâncias Intercalantes/farmacologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Nucleossomos/efeitos dos fármacos , Nucleossomos/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Transcriptoma/genética
17.
PLoS One ; 6(1): e16428, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21283538

RESUMO

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, regulating inflammatory and immune responses. MIF binds to cell surface receptor CD74, resulting in both rapid and sustained ERK activation. It was reported that MIF-induced rapid ERK activation requires its co-receptor CD44. But the exact mechanism underlying sustained ERK activation is not well understood. In the current study, we described a detailed mechanism of MIF mediated sustained ERK activation. We found that ß-arrestin1, a scaffold protein involved in the activation of the MAPK cascade, interacts with CD74 upon MIF stimulation, resulting in CD74-mediated MIF endocytosis in a chlorpromazine (CPZ)-sensitive manner. ß-arrestin1 is also involved in endocytotic MIF signaling, leading to sustained ERK activation. Therefore ß-arrestin1 plays a central role in coupling MIF endocytosis to sustained ERK activation.


Assuntos
Arrestinas/fisiologia , Endocitose , Fatores Inibidores da Migração de Macrófagos/fisiologia , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Linhagem Celular , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , beta-Arrestinas
18.
J Immunol ; 183(2): 1083-90, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19553546

RESUMO

MHC class I molecules present peptides from endogenous proteins. Ags can also be presented when derived from extracellular sources in the form of apoptotic bodies. Cross-presentation of such Ags by dendritic cells is required for proper CTL responses. The fate of Ags in cells initiated for apoptosis is unclear as is the mechanism of apoptosis-derived Ag transfer into dendritic cells. Here we show that novel Ags can be generated by caspases and be presented by MHC class I molecules of apoptotic cells. Since gap junctions function until apoptotic cells remodel to form apoptotic bodies, transfer and cross-presentation of apoptotic peptides by neighboring and dendritic cells occurs. We thus define a novel phase in classical Ag presentation and cross-presentation by MHC class I molecules: presentation of Ags created by caspase activities in cells in apoptosis.


Assuntos
Apresentação de Antígeno/imunologia , Apoptose/imunologia , Apresentação Cruzada , Junções Comunicantes/imunologia , Caspase 9/metabolismo , Caspases/metabolismo , Linhagem Celular , Técnicas de Cocultura , Conexina 43 , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos
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