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1.
Int J Mol Med ; 48(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34643251

RESUMO

Multiple myeloma (MM) is an aggressive B cell malignancy. Substantial progress has been made in the therapeutic context for patients with MM, however it still represents an incurable disease due to drug resistance and recurrence. Development of more effective or synergistic therapeutic approaches undoubtedly represents an unmet clinical need. Tomentosin is a bioactive natural sesquiterpene lactone extracted by various plants with therapeutic properties, including anti­neoplastic effects. In the present study, the potential antitumor activity of tomentosin was evaluated on the human RPMI­8226 cell line, treated with increasing tomentosin concentration for cytotoxicity screening. The data suggested that both cell cycle arrest and cell apoptosis could explain the antiproliferative effects of tomentosin and may result in the inhibition of RPMI­8226 cell viability. To assess differentially expressed genes contributing to tomentosin activity and identify its mechanism of action, a microarray gene expression profile was performed, identifying 126 genes deregulated by tomentosin. To address the systems biology and identify how tomentosin deregulates gene expression in MM from a systems perspective, all deregulated genes were submitted to enrichment and molecular network analysis. The Protein­Protein Interaction (PPI) network analysis showed that tomentosin in human MM induced the downregulation of genes involved in several pathways known to lead immune­system processes, such as cytokine­cytokine receptor interaction, chemokine or NF­κB signaling pathway, as well as genes involved in pathways playing a central role in cellular neoplastic processes, such as growth, proliferation, migration, invasion and apoptosis. Tomentosin also induced endoplasmic reticulum stress via upregulation of cyclic AMP­dependent transcription factor ATF­4 and DNA damage­inducible transcript 3 protein genes, suggesting that in the presence of tomentosin the protective unfolded protein response signaling may induce cell apoptosis. The functional connections analysis executed using the Connectivity Map tool, suggested that the effects of tomentosin on RPMI­8226 cells might be similar to those exerted by heat shock proteins inhibitors. Taken together, these data suggested that tomentosin may be a potential drug candidate for the treatment of MM.

2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445327

RESUMO

The fight against cancer is one of the main challenges for medical research. Recently, nanotechnology has made significant progress, providing possibilities for developing innovative nanomaterials to overcome the common limitations of current therapies. In this context, silver nanoparticles (AgNPs) represent a promising nano-tool able to offer interesting applications for cancer research. Following this path, we combined the silver proprieties with Artemisia arborescens characteristics, producing novel nanoparticles called Artemisia-AgNPs. A "green" synthesis method was performed to produce Artemisia-AgNPs, using Artemisia arborescens extracts. This kind of photosynthesis is an eco-friendly, inexpensive, and fast approach. Moreover, the bioorganic molecules of plant extracts improved the biocompatibility and efficacy of Artemisia-AgNPs. The Artemisia-AgNPs were fully characterized and tested to compare their effects on various cancer cell lines, in particular HeLa and MCF-7. Artemisia-AgNPs treatment showed dose-dependent growth inhibition of cancer cells. Moreover, we evaluated their impact on the cell cycle, observing a G1 arrest mediated by Artemisia-AgNPs treatment. Using a clonogenic assay after treatment, we observed a complete lack of cell colonies, which demonstrated cell reproducibility death. To have a broader overview on gene expression impact, we performed RNA-sequencing, which demonstrated the potential of Artemisia-AgNPs as a suitable candidate tool in cancer research.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Artemisia/química , Nanopartículas Metálicas , Prata , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/genética , Artemisia/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Química Verde , Células HeLa , Humanos , Células MCF-7 , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Células PC-3 , Extratos Vegetais/química , Prata/química , Prata/uso terapêutico
3.
Clin Epigenetics ; 13(1): 156, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372908

RESUMO

Skeletal muscle formation represents a complex of highly organized and specialized systems that are still not fully understood. Epigenetic systems underline embryonic development, maintenance of stemness, and progression of differentiation. Polycomb group proteins play the role of gene silencing of stemness markers that regulate muscle differentiation. Enhancer of Zeste EZH2 is the catalytic subunit of the complex that is able to trimethylate lysine 27 of histone H3 and induce silencing of the involved genes. In embryonal Rhabdomyosarcoma and several other tumors, EZH2 is often deregulated and, in some cases, is associated with tumor malignancy. This review explores the molecular processes underlying the failure of muscle differentiation with a focus on the PRC2 complex. These considerations could open new studies aimed at the development of new cutting-edge therapeutic strategies in the onset of Rhabdomyosarcoma.

4.
Eur J Med Chem ; 222: 113590, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34139625

RESUMO

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 µM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 µM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, ß-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.


Assuntos
Acrilonitrila/farmacologia , Antineoplásicos/farmacologia , Microtúbulos/efeitos dos fármacos , Triazóis/farmacologia , Acrilonitrila/química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Mitose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química
5.
J Cell Physiol ; 236(5): 3789-3799, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33089499

RESUMO

1,3,4-Oxadiazole derivatives are widely used in research on antineoplastic drugs. Recently, we discovered a novel unsymmetrical 1,3,4-oxadiazole compound with antiproliferative properties called 2j. To further investigate its possible targets and molecular mechanisms, RNA-seq was performed and the differentially expressed genes (DEGs) were obtained after treatment. Data were analyzed using functional (Gene Ontology term) and pathway (Kyoto Encyclopedia of Genes and Genomes) enrichment of the DEGs. The hub genes were determined by the analysis of protein-protein interaction networks. The connectivity map (CMap) information provided insight into the model action of antitumor small molecule drugs. Hub genes have been identified through function gene networks using STRING analysis. The small molecular targets obtained by CMap comparison showed that 2j is a tubulin inhibitor and it acts mainly affecting tumor cells through the cell cycle, FoxO signaling pathway, apoptotic, and p53 signaling pathways. The possible targets of 2j could be TUBA1A and TUBA4A. Molecular docking results indicated that 2j interacts at the colchicine-binding site on tubulin.

6.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339368

RESUMO

Small cell lung cancer (SCLC) is an aggressive type of lung cancer with high mortality that is caused by frequent relapses and acquired resistance. Despite that several target-based approaches with potential therapeutic impact on SCLC have been identified, numerous targeted drugs have not been successful in providing improvements in cancer patients when used as single agents. A combination of targeted therapies could be a strategy to induce maximum lethal effects on cancer cells. As a starting point in the development of new drug combination strategies for the treatment of SCLC, we performed a mid-throughput screening assay by treating a panel of SCLC cell lines with BETi or AKi in combination with PARPi or EZH2i. We observed drug synergy between I-BET762 and Talazoparib, BETi and PARPi, respectively, in SCLC cells. Combinatorial efficacy was observed in MYCs-amplified and MYCs-wt SCLC cells over SCLC cells with impaired MYC signaling pathway or non-tumor cells. We indicate that drug synergy between I-BET762 and Talazoparib is associated with the attenuation HR-DSBR process and the downregulation of various players of DNA damage response by BET inhibition, such as CHEK2, PTEN, NBN, and FANCC. Our results provide a rationale for the development of new combinatorial strategies for the treatment of SCLC.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Ftalazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Células Cultivadas , Dano ao DNA/efeitos dos fármacos , Sinergismo Farmacológico , Humanos
7.
Tumour Biol ; 42(2): 1010428319901061, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32013807

RESUMO

Burkitt lymphoma is a very aggressive B-cell non-Hodgkin lymphoma. Although remarkable progress has been made in the therapeutic scenario for patients with Burkitt lymphoma, search and development of new effective anticancer agents to improve patient outcome and minimize toxicity has become an urgent issue. In this study, the antitumoral activity of Inula viscosa, a traditional herb obtained from plants collected on the Asinara Island, Italy, was evaluated in order to explore potential antineoplastic effects of its metabolites on Burkitt lymphoma. Raji human cell line was treated with increasing Inula viscosa extract concentration for cytotoxicity screening and subsequent establishment of cell cycle arrest and apoptosis. Moreover, gene expression profiles were performed to identify molecular mechanisms involved in the anticancer activities of this medical plant. The Inula viscosa extract exhibited powerful antiproliferative and cytotoxic activities on Raji cell line, showing a dose- and time-dependent decrease in cell viability, obtained by cell cycle arrest in the G2/M phase and an increase in cell apoptosis. The treatment with Inula viscosa caused downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1) and inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A). The Inula viscosa extract causes strong anticancer effects on Burkitt lymphoma cell line. The molecular mechanisms underlying such antineoplastic activity are based on targeting and downregulation of genes involved in cell cycle and apoptosis. Our data suggest that Inula viscosa natural metabolites should be further exploited as potential antineoplastic agents against Burkitt lymphoma.


Assuntos
Linfoma de Burkitt/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Inula/química , Proteínas de Neoplasias/genética , Apoptose/efeitos dos fármacos , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia
8.
DNA Repair (Amst) ; 82: 102687, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476572

RESUMO

The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively. MBD4 is also involved in DNA damage response and transcriptional regulation. The interaction with other proteins is likely critical for understanding MBD4 functions. To identify novel proteins that interact with MBD4, we used tandem affinity purification (TAP) from HEK-293 cells. The MBD4-TAP fusion and its co-associated proteins were purified sequentially on IgG and calmodulin affinity columns; the final eluate was shown to contain MLH1 by western blotting, and MBD4-associated proteins were identified by mass spectrometry. Bands with molecular weight higher than that expected for MBD4 (˜66 kD) yielded peptides corresponding to MBD4 itself and the small ubiquitin-like molecule-1 (SUMO1), suggesting that MBD4 is sumoylated in vivo. MBD4 sumoylation was validated by co-immunoprecipitation in HEK-293 and MCF7 cells, and by an in vitrosumoylation assay. Sequence and mutation analysis identified three main sumoylation sites: MBD4 is sumoylated preferentially on K137, with additional sumoylation at K215 and K377. Patterns of MBD4 sumoylation were altered, in a DNA damage-specific way, by the anti-metabolite 5-fluorouracil, the alkylating agent N-Methyl-N-nitrosourea and the crosslinking agent cisplatin. MCF7 extract expressing sumoylated MBD4 displays higher thymine glycosylase activity than the unmodified species. Of the 67 MBD4 missense mutations reported in The Cancer Genome Atlas, 14 (20.9%) map near sumoylation sites. These results indicate that MBD4 is sumoylated in vivo in a DNA damage-specific manner, and suggest that sumoylation serves to regulate its repair activity and could be compromised in cancer. This study expands the role played by sumoylation in fine-tuning DNA damage response and repair.


Assuntos
Reparo do DNA , Endodesoxirribonucleases/metabolismo , Proteína SUMO-1/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Dano ao DNA , Endodesoxirribonucleases/química , Endodesoxirribonucleases/genética , Células HEK293 , Humanos , Células MCF-7 , Mutação , Neoplasias/genética , Sumoilação
9.
Chem Biol Interact ; 312: 108813, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494105

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric tumor, which arises from muscle precursor cells. Recently, it has been demonstrated that Hippo Pathway (Hpo), a pathway that regulates several physiological and biological features, is involved in RMS tumorigenesis. For instance, an upregulation of the Hpo downstream effector Yes-Associated Protein 1 (YAP) leads to the development of embryonal rhabdomyosarcoma (eRMS) in murine activated muscle satellite cells. On the other hand, the YAP paralog transcriptional co-activator with PDZ-binding motif (TAZ) is overexpressed in alveolar rhabdomyosarcoma (aRMS) patients with poor survival. YAP and TAZ exhibit both cytoplasmic and nuclear functions. In the nucleus, YAP binds TEADs (TEA domain family members) factors and together they constitute a complex that is able either to activate the transcription of several genes such as MYC, Tbx5 and PAX8 or to maintain the stability of others like p73. Due to the key role of YAP and TAZ in cancer, the identification and/or development of new compounds able to block their activity might be an effective antineoplastic strategy. Verteporfin (VP) is a molecule able to stop the formation of YAP/TEAD complex in the nucleus. The aim of this study is to evaluate the action of VP on RMS cell lines. This work shows that VP has an anti-proliferative activity on all RMS cell lines analyzed. Depending on RMS cell lines, VP affects cell cycle differently. Moreover, VP is able to decrease YAP protein levels, and to induce the activation of apoptosis mechanism through the cleavage of PARP-1. In addition, Annexin V assay showed the activation of apoptosis and necrosis after VP treatment. In summary, the ability of VP to disrupt RMS cell proliferation could be a novel and valuable strategy to improve the therapeutic approaches in treating rhabdomyosarcoma.


Assuntos
Proliferação de Células/efeitos dos fármacos , Verteporfina/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Fatores de Transcrição/metabolismo
10.
J Cell Physiol ; 233(9): 6508-6517, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29574790

RESUMO

Nowadays, epigenetics covers a crucial role in different fields of science. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), is a big proponent of how epigenetic changes can affect the initiation and progression of several diseases. Through its catalytic activity, responsible for the tri-methylation of lysine 27 of the histone H3 (H3K27me3), EZH2 is a good target for both diagnosis and therapy of different pathologies. A large number of studies have demonstrated its crucial role in cancer initiation and progression. Nevertheless, only recently its function in virus diseases has been uncovered; therefore, EZH2 can be an important promoter of viral carcinogenesis. This review explores the role of EZH2 in viral epigenetics based on recent progress that demonstrated the role of this protein in virus environment. In particular, the review focuses on EZH2 behavior in Hepatitis B Virus, analyzing its role in the rise of Hepatocellular Carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Epigênese Genética/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Animais , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Hepatite B/genética , Hepatite B/virologia , Humanos , Neoplasias Hepáticas/patologia
11.
J Cell Physiol ; 233(5): 4106-4115, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29023715

RESUMO

Cell proliferation assays are performed by four decades to test the anti-proliferative activity of natural products and synthetic compounds in cell cultures. In cancer research, they are widely employed to evaluate drug efficacy in in vitro tumor models, such as established cell lines, primary cultures, and recently developed three-dimensional tumor organoids. In this manuscript, we demonstrated that current employed parameters used by researchers to quantify in vitro growth inhibition, IC50 and GI50 , lead to a misinterpretation of results based on the exponential, and not linear, proliferation of the cells in culture. Therefore, we introduce a new parameter for the analysis of growth inhibition in cell proliferation assays, termed relative population doubling capacity, that can be employed to properly quantify the anti-proliferative activity of tested compounds and to compare drug efficacy between distinct cell models.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Organoides/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Cell Physiol ; 233(3): 2360-2365, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28722764

RESUMO

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma that arises from muscle precursors affecting predominately children and young adults. It can be divided into two main classes: embryonal (eRMS) and alveolar rhabodomyosarcomas (aRMS). Despite the expression of early muscle specific genes, RMS cells fail to complete myogenesis even in differentiation conditions. We previously demonstrated that Enhancer Zeste of Homolog 2 (EZH2), the catalytic subunits of PRC2 complex, contributes to inhibit muscle differentiation in eRMS and its down-regulation causes a partial recovery of myogenesis. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a molecule able to induce differentiation in eRMS with a mechanism that involves the protein kinase C (PKC). In this paper we report that treatment with TPA reduces the expression of EZH2 without affecting levels of H3K27me3. The combination of TPA with GSK126, an inhibitor of the catalytic activity of EZH2, has a synergic effect on the induction of muscle differentiation in RD rhabdomyosarcoma cells, suggesting a new therapeutic combinatory approach for RMS treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Desenvolvimento Muscular/efeitos dos fármacos , Piridonas/farmacologia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Acetato de Tetradecanoilforbol/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histonas/metabolismo , Humanos , Metilação , Rabdomiossarcoma Embrionário/metabolismo , Rabdomiossarcoma Embrionário/patologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
14.
J Med Chem ; 59(23): 10451-10469, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27801583

RESUMO

A series of novel 1,3,4-oxadiazoles was synthesized and evaluated for their cytotoxic activity in in vitro tumor models. Four of the new compounds (2d, 2j, 2k, and 2n) showed growth inhibition in the XTT dye assay. The most active agent, 2j, showed high potency against human cancer cells with IC50s ranging from 0.05 to 1.7 µM. Preliminary SAR correlations suggested that the nature of chains on the oxadiazole is important for antitumor potency in vitro. Compound 2j determined a G2/M arrest of the cell cycle and also activated a strong apoptotic response. The ß-tubulin immunofluorescence analysis indicated that compound 2j effectively inhibited the microtubule organization in all cancer cell lines, causing the formation of abnormal spindle, which did not affect the normal human fibroblast cells NB1, Mrc-5 and IBR3. For all these reasons, compound 2j could be a good candidate in chemopreventive or chemotherapeutic strategies.


Assuntos
Antineoplásicos/farmacologia , Oxidiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade
15.
World J Clin Oncol ; 7(2): 135-48, 2016 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-27081636

RESUMO

Polycomb group proteins represent a global silencing system involved in development regulation. In specific, they regulate the transition from proliferation to differentiation, contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, which induces transcriptional inhibition through the tri-methylation of histone H3, an epigenetic change associated with gene silencing. EZH2 expression is high in precursor cells while its level decreases in differentiated cells. EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis. Indeed, aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes, resulting in an uncontrolled proliferation and tumor formation. This editorial explores the role of Polycomb repressive complex 2 in cancer, focusing in particular on EZH2. The canonical function of EZH2 in gene silencing, the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation, were summarized. Moreover, mutations of EZH2, responsible for an increased methyltransferase activity in cancer, were recapitulated. Finally, various drugs able to inhibit EZH2 with different mechanism were described, specifically underscoring the effects in several cancers, in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

16.
Clin Cancer Res ; 22(13): 3398-409, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27076624

RESUMO

PURPOSE: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations. EXPERIMENTAL DESIGN: Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays. RESULTS: PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas. CONCLUSIONS: Our work reveals a novel PML-I-TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398-409. ©2016 AACR.


Assuntos
Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/patologia , Neuroblastoma/patologia , Proteína da Leucemia Promielocítica/metabolismo , Trombospondinas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/genética , Crista Neural/embriologia , Neuroblastoma/genética , Proteína da Leucemia Promielocítica/genética , Isoformas de Proteínas/genética , Fatores de Risco , Células-Tronco/citologia , Sistema Nervoso Simpático/embriologia , Trombospondinas/genética , Proteínas Supressoras de Tumor/genética
17.
Cell Cycle ; 13(4): 516-27, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24496329

RESUMO

Polycomb group proteins represent a global silencing system involved in embryonic development and stem-cell maintenance that regulates the transition from proliferation to differentiation during organogenesis. Two main complexes have been discovered: the polycomb repressive complex (PRC) 1 and 2, able to induce gene silencing by a synergistic mechanism or independently by each other. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represses gene transcription through the tri-methylation of histone H3 lysine 27. EZH2 deregulation is frequently associated with tumorigenesis, metastatic character, and poor prognosis in various cancer types. This review explores the role of EZH2 in normal development and in carcinogenesis. We reviewed the polycomb-mediated silencing mechanisms, the regulation of EZH2 activity and its recruitment to target genes. We also analyzed the role of EZH2 in normal muscle differentiation and in rhabdomyosarcoma, considering EZH2 blockade as a new strategy for developing specific therapies.


Assuntos
Carcinogênese/patologia , Músculo Esquelético/citologia , Complexo Repressor Polycomb 2/metabolismo , Rabdomiossarcoma/patologia , Animais , Carcinogênese/metabolismo , Diferenciação Celular , Epigênese Genética , Inativação Gênica , Histonas/metabolismo , Humanos , MicroRNAs/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo
18.
Age (Dordr) ; 36(1): 9-20, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23653328

RESUMO

Recent evidence suggests that ageing-related diseases could result in an accelerated loss of self-renewal capability of adult stem cells, normally involved in replacing damaged cellular elements. In previous works, we highlighted that a specific treatment, named tissue optimization-regenerative (TO-RGN), of radio-electric asymmetric conveyer (REAC) technology, influenced gene expression profiles controlling stem cell differentiation and pluripotency of human skin-derived fibroblasts in vitro. The purpose of the present work was to verify whether TO-RGN may also be effective in counteracting the expression of the senescence marker beta-galactosidase and of senescence-associated gene expression patterning, engaged during prolonged culture of human adipose-derived stem cells (hADSCs). Following TO-RGN exposure, we observed a significant downregulation in beta-galactosidase staining and in the expression of the senescence mediator genes p16INK4, ARF, p53, and p21(CIP1). Moreover, differently formed untreated cells, TO-RGN-exposed hADSCs maintained their typical fibroblast-like morphology and exhibited a multilineage potential even at late passages, as shown by the remarkable preservation of commitment to osteogenic, adipogenic, chondrogenic, and vasculogenic fates, both at morphologic and gene expression levels. In conclusion, our study highlights a positive effect of TO-RGN in counteracting degenerative senescence processes in vitro.


Assuntos
Senescência Celular/efeitos da radiação , Estimulação Elétrica , Células-Tronco/citologia , Tecido Adiposo/citologia , Diferenciação Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Senescência Celular/genética , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Coloração e Rotulagem , Regulação para Cima , beta-Galactosidase/metabolismo
19.
Drug Des Devel Ther ; 7: 1063-73, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24101862

RESUMO

Mouse embryonic stem cells were previously observed along with mesenchymal stem cells from different sources, after being treated with a mixed ester of hyaluronan with butyric and retinoic acids, to show a significant increase in the yield of cardiogenic and vascular differentiated elements. The aim of the present study was to determine if stem cells derived from primitive fetal cells present in human amniotic fluid (hAFSCs) and cultured in the presence of a mixture of hyaluronic (HA), butyric (BU), and retinoic (RA) acids show a higher yield of differentiation toward the cardiovascular phenotype as compared with untreated cells. During the differentiation process elicited by exposure to HA + BU + RA, genes controlling pluripotency and plasticity of stem cells, such as Sox2, Nanog, and Oct4, were significantly downregulated at the transcriptional level. At this point, a significant increase in expression of genes controlling the appearance of cardiogenic and vascular lineages in HA + BU + RA-treated cells was observed. The protein expression levels typical of cardiac and vascular phenotypes, evaluated by Western blotting, immunofluorescence, and flow cytometry, were higher in hAFSCs cultured in the presence of HA + BU + RA, as compared with untreated control cells. Appearance of the cardiac phenotype was further inferred by ultrastructural analysis using transmission and scanning electron microscopy. These results demonstrate that a mixture of HA + BU + RA significantly increased the yield of elements committed toward cardiac and vascular phenotypes, confirming what we have previously observed in other cellular types.


Assuntos
Líquido Amniótico/citologia , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células-Tronco/metabolismo , Vasos Sanguíneos/citologia , Western Blotting , Ácido Butírico/química , Ácido Butírico/farmacologia , Células Cultivadas , Citometria de Fluxo , Imunofluorescência , Proteínas de Homeodomínio/genética , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Miocárdio/citologia , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/genética , Fenótipo , Fatores de Transcrição SOXB1/genética , Tretinoína/química , Tretinoína/farmacologia
20.
J Cell Physiol ; 228(5): 945-51, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23086732

RESUMO

Lung cancer is the leading cause of cancer-related deaths over the world, characterized by a very high mortality rate. Molecular technique development tries to focus on early detection of cancers by studying molecular alterations that characterize cancer cells. Worldwide lung cancer research has focused on an ever-increasing number of molecular elements of carcinogenesis at genetic, epigenetic and protein levels. The non-invasiveness is the characteristic that all clinical trials on cancer detection should have. Abnormal chest imaging and/or non-specific symptoms are initial signals of lung cancer that appear in an advanced stage of disease. This fact represents the cause of the low 5-year survival rate: over 90% of patients dying within 5 years of diagnosis. Since smokers have higher quantity of sputum containing exfoliated cells from the bronchial tree, and the sputum represents the most easily accessible biological fluid and its collection is non-invasive, analysis of this sample represents a good area of research in early lung cancer diagnosis. Continued cigarette smoking is the cause of chronic obstructive pulmonary disease (COPD), with an estimated attributable risk factor exceeding 80% in smoking affected individuals. Lung cancer is found in 40-70% of patients with COPD, particularly in severe disease, and it is a common cause of death in these patients. A large prospective trial of almost half a million non-smokers showed as lung cancer is also common in patients with COPD who have never smoked. This review describes issues related to early lung cancer screening using non-invasive methods.


Assuntos
Detecção Precoce de Câncer , Neoplasias Pulmonares , Escarro , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco , Fumar , Escarro/citologia , Escarro/metabolismo , Taxa de Sobrevida
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