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1.
Nat Commun ; 14(1): 7291, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37968277

RESUMO

Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.


Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Animais , Criança , Humanos , Camundongos , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica , Músculo Esquelético/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma Alveolar/genética
3.
EMBO Rep ; 22(12): e53085, 2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34779563

RESUMO

All living organisms have developed processes to sense and address environmental changes to maintain a stable internal state (homeostasis). When activated, the p53 tumour suppressor maintains cell and organ integrity and functions in response to homeostasis disruptors (stresses) such as infection, metabolic alterations and cellular damage. Thus, p53 plays a fundamental physiological role in maintaining organismal homeostasis. The TP53 gene encodes a network of proteins (p53 isoforms) with similar and distinct biochemical functions. The p53 network carries out multiple biological activities enabling cooperation between individual cells required for long-term survival of multicellular organisms (animals) in response to an ever-changing environment caused by mutation, infection, metabolic alteration or damage. In this review, we suggest that the p53 network has evolved as an adaptive response to pathogen infections and other environmental selection pressures.


Assuntos
Genes p53 , Homeostase , Proteína Supressora de Tumor p53 , Animais , Infecções , Mutação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Nat Commun ; 12(1): 5520, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535684

RESUMO

PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.


Assuntos
Fator de Transcrição PAX7/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Animais , Cruzamento , Diferenciação Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Integrases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Desenvolvimento Muscular , PTEN Fosfo-Hidrolase/deficiência , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Rabdomiossarcoma/genética
5.
Australas J Dermatol ; 62(3): 292-299, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34117779

RESUMO

BACKGROUND/OBJECTIVES: Vulval lichen sclerosus (VLS) is a chronic inflammatory skin condition predominantly affecting the anogenital region in women and children. To date, there is lack of agreement amongst experts on a severity scale to aid assessment, research and treatment stratification on VLS. Furthermore, literature on best practice for long-term management of VLS is lacking. The aim of this consensus is to provide broad guidelines on the short and long-term management of VLS. METHODS: An initial focus group of Australasian experts in vulval dermatology developed a draft consensus statement for the management of VLS. Based on the results of the draft statement, a consensus panel of 22 Australasian experts, comprised of the initial and additional members, participated in an anonymous four-stage eDelphi process. Round 1 involved generation and voting on statements from the draft consensus statement developed by the focus group. In Rounds 2, 3 & 4, panel members were presented formal feedback from previous rounds and asked to indicate their level of agreement. Consensus was reached if there was ≥70% agreement on the importance of an item in the 4 (agree) to 5 (strongly agree) range. RESULTS: The expert panel, with a total of 504 collective years of experience in the field of VLS, reached consensus on a core set of 51 management statements related to diagnosis, severity, initial and long-term management, follow-up, and complications of VLS. CONCLUSIONS: This study has identified a set of management statements for VLS that may be useful in clinical practice in the Australasian population.


Assuntos
Consenso , Líquen Escleroso e Atrófico/terapia , Guias de Prática Clínica como Assunto/normas , Padrões de Prática Médica/normas , Líquen Escleroso Vulvar/terapia , Dermatologistas/normas , Feminino , Humanos , Líquen Escleroso e Atrófico/prevenção & controle , Líquen Escleroso Vulvar/prevenção & controle
6.
Molecules ; 26(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494466

RESUMO

Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, N-[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos , DNA de Neoplasias/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores da Topoisomerase II , Adenocarcinoma de Pulmão/história , Adenocarcinoma de Pulmão/metabolismo , Amsacrina/química , Amsacrina/história , Amsacrina/farmacocinética , Amsacrina/uso terapêutico , Anáfase/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/história , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Cromátides/metabolismo , Segregação de Cromossomos/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , História do Século XX , História do Século XXI , Humanos , Neoplasias Pulmonares/história , Neoplasias Pulmonares/metabolismo , Camundongos , Naftiridinas/química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacocinética , Inibidores da Topoisomerase II/uso terapêutico
7.
Cancers (Basel) ; 12(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882831

RESUMO

We investigated the influence of selected TP53 SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.34-5.35-fold greater risk of developing cancer. These SNP combinations were found to be associated with shorter patient survival for glioblastoma and prostate cancer. Additionally, these SNPs were associated with tumor-promoting inflammation as evidenced by high levels of infiltrating immune cells and expression of the Δ133TP53 and TP53ß transcripts. We propose that these SNP combinations allow increased expression of the Δ133p53 isoforms to promote the recruitment of immune cells that create an immunosuppressive environment leading to cancer progression.

8.
Cell Death Dis ; 10(9): 631, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431617

RESUMO

Prostate cancer is the second most common cancer in men, for which there are no reliable biomarkers or targeted therapies. Here we demonstrate that elevated levels of Δ133TP53ß isoform characterize prostate cancers with immune cell infiltration, particularly T cells and CD163+ macrophages. These cancers are associated with shorter progression-free survival, Gleason scores ≥ 7, and an immunosuppressive environment defined by a higher proportion of PD-1, PD-L1 and colony-stimulating factor 1 receptor (CSF1R) positive cells. Consistent with this, RNA-seq of tumours showed enrichment for pathways associated with immune signalling and cell migration. We further show a role for hypoxia and wild-type p53 in upregulating Δ133TP53 levels. Finally, AUC analysis showed that Δ133TP53ß expression level alone predicted aggressive disease with 88% accuracy. Our data identify Δ133TP53ß as a highly accurate prognostic factor for aggressive prostate cancer.


Assuntos
Neoplasias da Próstata/imunologia , Proteína Supressora de Tumor p53/imunologia , Células A549 , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Humanos , Células MCF-7 , Macrófagos/imunologia , Masculino , Células PC-3 , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Isoformas de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética
10.
Mol Cell Oncol ; 5(4): e1448246, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30250910

RESUMO

Rhabdomyosarcoma (RMS) histologically resembles developing skeletal muscle and is thought to solely originate from a differentiation block in muscle progenitors. We demonstrate that RMS can arise from endothelial progenitor cells following reprogramming and myogenic transdifferentiation. These results highlight how tumors with identical morphological features can arise from different cell types and offer insight into RMS formation in non-myogenic tissue.

11.
Nat Commun ; 9(1): 2071, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789663

RESUMO

The original PDF version of this Article listed the authors as "Marcus J.G.W. Ladds," where it should have read "Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#".Also in the PDF version, it was incorrectly stated that "Correspondence and requests for materials should be addressed to S. Lín.", instead of the correct "Correspondence and requests for materials should be addressed to S. Laín."This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.

12.
PLoS One ; 13(4): e0195956, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29684045

RESUMO

Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Benzamidas/farmacologia , Indóis/farmacologia , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/farmacologia , Antineoplásicos/química , Benzamidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Estrutura Molecular , Mutação , Sirtuínas/genética , Proteína Supressora de Tumor p53/genética , Vemurafenib
13.
Nat Commun ; 9(1): 1107, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29549331

RESUMO

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Neoplasias/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Di-Hidro-Orotato Desidrogenase , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Proteólise/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
14.
Cancer Cell ; 33(1): 108-124.e5, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29316425

RESUMO

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that histologically resembles embryonic skeletal muscle. RMS occurs throughout the body and an exclusively myogenic origin does not account for RMS occurring in sites devoid of skeletal muscle. We previously described an RMS model activating a conditional constitutively active Smoothened mutant (SmoM2) with aP2-Cre. Using genetic fate mapping, we show SmoM2 expression in Cre-expressing endothelial progenitors results in myogenic transdifferentiation and RMS. We show that endothelium and skeletal muscle within the head and neck arise from Kdr-expressing progenitors, and that hedgehog pathway activation results in aberrant expression of myogenic specification factors as a potential mechanism driving RMS genesis. These findings suggest that RMS can originate from aberrant development of non-myogenic cells.


Assuntos
Endotélio/metabolismo , Proteínas Hedgehog/metabolismo , Desenvolvimento Muscular/genética , Rabdomiossarcoma/metabolismo , Células-Tronco/metabolismo , Animais , Diferenciação Celular/fisiologia , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Transdução de Sinais
15.
Cancer Res ; 77(22): 6109-6118, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28916654

RESUMO

Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Because of the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to miRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here, we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma. miR-23 target genes, including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis, were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis. Cancer Res; 77(22); 6109-18. ©2017 AACR.


Assuntos
RNA Helicases DEAD-box/genética , Predisposição Genética para Doença/genética , Hemangiossarcoma/genética , Mutação , Ribonuclease III/genética , Animais , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Hemangiossarcoma/patologia , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética
16.
Australas J Dermatol ; 58(2): 155-159, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28251611

RESUMO

Although most infantile haemangiomas do not require treatment due to a natural history of spontaneous involution, some require early intervention. The Australasian Vascular Anomalies Network and the Australasian Paediatric Dermatology Network have developed a consensus statement for the treatment of infantile haemangiomas with oral propranolol. Infants with haemangiomas that are life threatening, at risk of ulceration, or at risk of causing a significant functional impairment, psychological impact or physical deformity should be treated early with oral propranolol. Oral propranolol is safe and effective and in most healthy infants oral propranolol can be started in an outpatient setting.


Assuntos
Consenso , Hemangioma Capilar/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Propranolol/uso terapêutico , Vasodilatadores/uso terapêutico , Monitoramento de Medicamentos , Humanos , Seleção de Pacientes , Propranolol/administração & dosagem , Vasodilatadores/administração & dosagem
17.
Oncotarget ; 7(29): 46203-46218, 2016 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-27323823

RESUMO

Non-genotoxic reactivation of the p53 pathway by MDM2-p53 binding antagonists is an attractive treatment strategy for wild-type TP53 cancers. To determine how resistance to MDM2/p53 binding antagonists might develop, SJSA-1 and NGP cells were exposed to growth inhibitory concentrations of chemically distinct MDM2 inhibitors, Nutlin-3 and MI-63, and clonal resistant cell lines generated. The p53 mediated responses of parental and resistant cell lines were compared. In contrast to the parental cell lines, p53 activation by Nutlin-3, MI-63 or ionizing radiation was not observed in either the SJSA-1 or the NGP derived cell lines. An identical TP53 mutation was subsequently identified in both of the SJSA-1 resistant lines, whilst one out of three identified mutations was common to both NGP derived lines. Mutation specific PCR revealed these mutations were present in parental SJSA-1 and NGP cell populations at a low frequency. Despite cross-resistance to a broad panel of MDM2/p53 binding antagonists, these MDM2-amplified and TP53 mutant cell lines remained sensitive to ionizing radiation (IR). These results indicate that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Humanos , Mutação , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
18.
Australas J Dermatol ; 57(4): 253-263, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26148424

RESUMO

Vulvodynia is a common and debilitating chronic pain syndrome characterised by neuropathic-type pain. Localised provoked vulvodynia is the most common type, followed by generalised unprovoked vulvodynia. Vulvodynia is a diagnosis of exclusion. The cause is unknown but current research suggests an underlying predisposition to increased sensitivity to pain and peripheral and central neural sensitisation. Musculoskeletal factors also play an important role. Vulvodynia has a significant impact on the quality of life, mood, functional ability and relationships of patients and their partners. It is highly associated with anxiety and depression. Treatment needs to follow a biopsychosocial model and be tailored to the patient. A multimodal and multidisciplinary approach is often most effective. We have suggested a therapeutic ladder.

19.
Oncotarget ; 6(18): 16488-506, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26029997

RESUMO

Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor auranofin, which is FDA-approved and currently in clinical trials against leukemia and a number of solid cancers, displayed effects comparable with MJ25 on cells and led to eradication of cultured melanoma cells at low micromolar concentrations. In conclusion, auranofin, MJ25 or other inhibitors of TrxR1 should be evaluated as candidate compounds or leads for targeted therapy of malignant melanoma.


Assuntos
Benzotiazóis/farmacologia , Benzoxazóis/farmacologia , Ativação Enzimática/efeitos dos fármacos , Imidazóis/farmacologia , Melanoma/tratamento farmacológico , Piperazinas/farmacologia , Sulfonas/farmacologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Auranofina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Glutationa/metabolismo , Glutationa Redutase/antagonistas & inibidores , Células HCT116 , Humanos , Indóis/farmacologia , Melanoma/patologia , Camundongos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Proteína Supressora de Tumor p53/genética , Vemurafenib
20.
Oncotarget ; 6(25): 21016-28, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26023799

RESUMO

We have shown earlier that overexpression of the human mitochondrial ribosomal protein MRPS18-2 (S18-2) led to immortalization of primary rat embryonic fibroblasts. The derived cells expressed the embryonic stem cell markers, and cellular pathways that control cell proliferation, oxidative phosphorylation, cellular respiration, and other redox reactions were activated in the immortalized cells.Here we report that, upon overexpression of S18-2 protein, primary rat skin fibroblasts underwent cell transformation. Cells passed more than 300 population doublings, and two out of three tested clones gave rise to tumors in experimental animals. Transformed cells showed anchorage-independent growth and loss of contact inhibition; they expressed epithelial markers, such as E-cadherin and ß-catenin. Transformed cells showed increased telomerase activity, disturbance of the cell cycle, and chromosomal instability. Taken together, our data suggest that S18-2 is a newly identified oncoprotein that may be involved in cancerogenesis.


Assuntos
Transformação Celular Neoplásica , Fibroblastos/metabolismo , Proteínas Ribossômicas/metabolismo , Pele/metabolismo , Animais , Carcinogênese , Proliferação de Células , Instabilidade Cromossômica , Citometria de Fluxo , Proteínas de Fluorescência Verde/metabolismo , Humanos , Cariotipagem , Lipídeos/química , Camundongos , Camundongos SCID , Mitocôndrias/metabolismo , Oxirredução , Oxigênio/química , Ratos , Telomerase/metabolismo
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