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1.
PLoS One ; 15(7): e0225351, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735563

RESUMO

Endothelial cilia are found in a variety of tissues including the cranial vasculature of zebrafish embryos. Recently, endothelial cells in the developing mouse retina were reported to also possess primary cilia that are potentially involved in vascular remodeling. Fish carrying mutations in intraflagellar transport (ift) genes have disrupted cilia and have been reported to have an increased rate of spontaneous intracranial hemorrhage (ICH), potentially due to disruption of the sonic hedgehog (shh) signaling pathway. However, it remains unknown whether the endothelial cells forming the retinal microvasculature in zebrafish also possess cilia, and whether endothelial cilia are necessary for development and maintenance of the blood-retinal barrier (BRB). In the present study, we found that the endothelial cells lining the zebrafish hyaloid vasculature possess primary cilia during development. To determine whether endothelial cilia are necessary for BRB integrity, ift57, ift88, and ift172 mutants, which lack cilia, were crossed with the double-transgenic zebrafish strain Tg(l-fabp:DBP-EGFP;flk1:mCherry). This strain expresses a vitamin D-binding protein (DBP) fused to enhanced green fluorescent protein (EGFP) as a tracer in the blood plasma, while the endothelial cells forming the vasculature are tagged by mCherry. The Ift mutant fish develop a functional BRB, indicating that endothelial cilia are not necessary for early BRB integrity. Additionally, although treatment of zebrafish larvae with Shh inhibitor cyclopamine results in BRB breakdown, the Ift mutant fish were not sensitized to cyclopamine-induced BRB breakdown.


Assuntos
Barreira Hematorretiniana/metabolismo , Cílios/metabolismo , Células Endoteliais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Geneticamente Modificados , Barreira Hematorretiniana/efeitos dos fármacos , Barreira Hematorretiniana/fisiologia , Células Endoteliais/citologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Larva/metabolismo , Mutagênese , Vasos Retinianos/citologia , Transdução de Sinais , Alcaloides de Veratrum/farmacologia , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
2.
Life Sci ; 254: 117695, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407849

RESUMO

AIMS: To investigate the therapeutic potential of itraconazole in oral squamous cell carcinoma (OSCC) and its molecular mechanism. MATERIALS AND METHODS: The in vitro anti-cancer effects of itraconazole was determined by CCK-8 assay and colony formation assay. Transwell and wound healing assays were used to examine cell invasion and migration. The in vivo therapeutic efficacy of itraconazole was assessed by OSCC patient-derived xenograft (PDX) model. Western blot was performed to explore the anti-cancer mechanism. KEY FINDINGS: Itraconazole inhibited cell proliferation and colony formation of OSCC cells in a time and concentration dependent manner; induced cell cycle arrest and apoptosis, as well as inhibited cell invasion and migration. In the OSCC PDX model, itraconazole impeded tumor growth, reduced Ki-67 expression and induced apoptosis. Itraconazole downregulated the protein expression of Hedgehog pathway to inhibit proliferation and migration of oral squamous cell carcinoma cells, which can be revised by recombinant human sonic hedgehog protein (rSHH). SIGNIFICANCE: Itraconazole showed anti-cancer effects on OSCC via inhibiting the Hedgehog pathway.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Proteínas Hedgehog/antagonistas & inibidores , Itraconazol/farmacologia , Neoplasias Bucais/patologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Bucais/metabolismo
5.
Anticancer Res ; 40(3): 1451-1458, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132042

RESUMO

BACKGROUND/AIM: Resistance to chemotherapeutic agents is the main cause of reduced survival in non-small cell lung cancer (NSCLC) patients. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemotherapy resistance. MATERIALS AND METHODS: HCC827 NSCLC cells were treated with sub-lethal doses of pemetrexed to produce pemetrexed resistance. RT-qPCR was performed to measure gene expression of HH pathway proteins. A cell growth assay was used to measure the impact of the HH-inhibitor Gant61 in naïve and chemoresistant cell lines. RESULTS: Pemetrexed resistant cells showed significantly increased expression of HH signaling genes (GLI1, GLI2, GLI3, PTCH1, SHH). Supporting these results, pemetrexed resistant cells treated with the HH inhibitor Gant61 showed reduced proliferation compared to naïve cells. CONCLUSION: HH pathway may play an important role in mediating pemetrexed resistance in NSCLC cells. Blocking the HH pathway may be a potential option to overcome this resistance.


Assuntos
Proteínas Hedgehog/metabolismo , Pemetrexede/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais
6.
Int J Nanomedicine ; 15: 1215-1228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110018

RESUMO

Background: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity. Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab') antibody fragments to enable targeted delivery of Egm. Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm. Conclusion: This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.


Assuntos
Autoimunidade/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Nanopartículas/administração & dosagem , Pirimidinonas/administração & dosagem , Linfócitos T/efeitos dos fármacos , Tiofenos/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Fragmentos de Imunoglobulinas/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Doenças Reumáticas/imunologia , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
7.
PLoS Biol ; 18(2): e3000620, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32053600

RESUMO

Primary cilia are lost during cancer development, but the mechanism regulating cilia degeneration is not determined. While transcription factor nuclear factor-erythroid 2-like 2 (NRF2) protects cells from oxidative, proteotoxic, and metabolic stress in normal cells, hyperactivation of NRF2 is oncogenic, although the detailed molecular mechanisms by which uncontrolled NRF2 activation promotes cancer progression remain unclear. Here, we report that NRF2 suppresses hedgehog (Hh) signaling through Patched 1 (PTCH1) and primary ciliogenesis via p62/sequestosome 1 (SQSTM1). PTCH1, a negative regulator of Hh signaling, is an NRF2 target gene, and as such, hyperactivation of NRF2 impairs Hh signaling. NRF2 also suppresses primary cilia formation through p62-dependent inclusion body formation and blockage of Bardet-Biedl syndrome 4 (BBS4) entrance into cilia. Simultaneous ablation of PTCH1 and p62 completely abolishes NRF2-mediated inhibition of both primary ciliogenesis and Hh signaling. Our findings reveal a previously unidentified role of NRF2 in controlling a cellular organelle, the primary cilium, and its associated Hh signaling pathway and also uncover a mechanism by which NRF2 hyperactivation promotes tumor progression via primary cilia degeneration and aberrant Hh signaling. A better understanding of the crosstalk between NRF2 and primary cilia/Hh signaling could not only open new avenues for cancer therapeutic discovery but could also have significant implications regarding pathologies other than cancer, including developmental disorders, in which improper primary ciliogenesis and Hh signaling play a major role.


Assuntos
Cílios/fisiologia , Proteínas Hedgehog/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Elementos de Resposta Antioxidante , Células Cultivadas , Cílios/metabolismo , Expressão Gênica , Técnicas de Inativação de Genes , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Corpos de Inclusão/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais
8.
Expert Opin Pharmacother ; 21(5): 523-530, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32027196

RESUMO

Introduction: Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.Areas covered: The current paper reviews the clinical development of glasdegib, a selective inhibitor of the Hedgehog signaling pathway through binding to its target SMO, for the treatment of AML.Expert opinion: Glasdegib confirmed its efficacy and showed an acceptable tolerability, especially when used in combination either with '3 + 7' chemotherapy or with low-intensity therapies. In 2018, glasdegib was approved by the Food and Drug Administration (FDA) in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients older than 75 years or presenting with severe comorbidities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Citarabina/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Transdução de Sinais , Estados Unidos , United States Food and Drug Administration
9.
Adv Anat Pathol ; 27(2): 98-111, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31895095

RESUMO

Basal cell carcinoma (BCC) of the skin is the most common type of malignant human tumor. However, metastatic BCC is a very rare event with weakly effective therapeutic options and a poor prognosis, until a few years ago. In 2012, small-molecule therapies, capable of inactivating the hedgehog signaling pathway and thus reducing tumor growth and progression, were introduced into clinical practice for the treatment of patients with advanced BCC. We present retrospectively 2 personal cases of metastatic BCC of the skin, from the premolecular therapy era, from primary tumors that arose years before in the head and neck area. The former case occurred in a 45-year-old woman with a history of recurrent BCC of the retroauricular skin who eventually died due to diffuse metastatic spread. The latter case concerned a 70-year-old man also with a history of recurrent BCC of the nasal-perinasal skin who developed multiple subcutaneous and lymph node metastases in the neck. In both cases, the diagnoses were based on biopsies of the metastatic sites. The first patient died 5 months after the diagnosis of metastatic disease, while the second was alive and disease-free 2 years after neck lymph node dissection and external radiation therapy, and then lost to follow-up. We extensively discuss several tumor entities with basal or basaloid features that may enter the differential diagnosis with BCC in metastatic sites. In addition, we briefly summarize the advances in clinical therapeutics using small molecules, which are now an integral part of the treatment of such advanced BCC cases.


Assuntos
Carcinoma Basocelular/patologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Adulto , Idoso , Carcinoma Basocelular/diagnóstico por imagem , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/metabolismo , Diagnóstico Diferencial , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Metástase Linfática/diagnóstico por imagem , Masculino , Recidiva Local de Neoplasia/patologia , Cintilografia , Estudos Retrospectivos , Bibliotecas de Moléculas Pequenas/uso terapêutico
10.
Cell Commun Signal ; 17(1): 172, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31878932

RESUMO

Uncontrolled activation of the Hedgehog/Glioma-associated oncogene (HH/GLI) pathway is a potent oncogenic driver signal promoting numerous cancer hallmarks such as proliferation, survival, angiogenesis, metastasis and metabolic rewiring. Several HH pathway inhibitors have already been approved for medical therapy of advanced and metastatic basal cell carcinoma and acute myeloid leukemia with partially impressive therapeutic activity. However, de novo and acquired resistance as well as severe side effects and unexplained lack of therapeutic efficacy are major challenges that urgently call for improved treatment options with more durable responses. The recent breakthroughs in cancer immunotherapy have changed our current understanding of targeted therapy and opened up promising therapeutic opportunities including combinations of selective cancer pathway and immune checkpoint inhibitors. Although HH/GLI signaling has been intensely studied with respect to the classical hallmarks of cancer, its role in the modulation of the anti-tumoral immune response has only become evident in recent studies. These have uncovered HH/GLI regulated immunosuppressive mechanisms such as enhanced regulatory T-cell formation and production of immunosuppressive cytokines. In light of these exciting novel data on oncogenic HH/GLI signaling in immune cross-talk and modulation, we summarize and connect in this review the existing knowledge from different HH-related cancers and chronic inflammatory diseases. This is to provide a basis for the investigation and evaluation of novel treatments combining immunotherapeutic strategies with approved as well as next-generation HH/GLI inhibitors. Further, we also critically discuss recent studies demonstrating a possible negative impact of current HH/GLI pathway inhibitors on the anti-tumoral immune response, which may explain some of the disappointing results of several oncological trials with anti-HH drugs. Additional file 1Video abstract. (9500 kb).


Assuntos
Carcinoma/imunologia , Proteínas Hedgehog/metabolismo , Leucemia Mieloide Aguda/imunologia , Transdução de Sinais , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma/terapia , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Imunoterapia , Leucemia Mieloide Aguda/terapia , Transdução de Sinais/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores
11.
Nat Commun ; 10(1): 5829, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863004

RESUMO

Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.


Assuntos
Neoplasias Cerebelares/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Hedgehog/antagonistas & inibidores , Meduloblastoma/genética , Transdução de Sinais/genética , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias Cerebelares/tratamento farmacológico , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Feminino , Mutação com Ganho de Função , Proteínas Hedgehog/genética , Humanos , Masculino , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular/métodos , Proteína MyoD/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Receptor Smoothened/genética , Fatores de Transcrição HES-1/genética
13.
Drug Resist Updat ; 47: 100646, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31733611

RESUMO

For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will benefit from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Inibidores de Proteassoma/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores
14.
Life Sci ; 236: 116933, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614146

RESUMO

AIMS: Hepatocellular carcinoma (HCC) pathogenesis involves the interplay of multiple signalling pathways. Notch and Hedgehog (Hh) are two major developmental pathways that act in concert to regulate adult cell repair. CK2α -serine-threonine kinase-down-regulation enhanced apoptotic activity and was proven beneficial for HCC patients. Quercetin is a bioactive flavonoid and has been shown to protect against HCC through its antioxidant activity. This study was carried out to elucidate the antineoplastic effect of quercetin through regulating both Notch and Hh pathways, apoptosis, cell proliferation and CK2α activity. MAIN METHODS: Hepatocellular carcinoma was induced in male Sprague Dawley rats by thioacetamide. Quercetin was administered in both protective and curative doses. Parameters of liver function and oxidative stress were assessed. CK2α, Notch and Hh pathways were evaluated using RT-PCR and ELISA. Apoptosis was investigated by detecting caspase-3, caspase-8 and p53. Proliferative and cell cycle markers as cyclin D1 and Ki-67 were detected immunohistochemically. KEY FINDINGS: Quercetin inhibited CK2α and downregulated mRNA and protein expression of Notch1 and Gli2. Quercetin also suppressed caspase-3 expression but not caspase-8. Quercetin elevated p53 expression whereas proliferative and cell cycle markers cyclin D1 and Ki-67 were downregulated. Markers of hepatic cellular integrity such as AST, ALT, ALP, GGT, albumin and bilirubin were significantly ameliorated. This was confirmed by histological examination. Quercetin also alleviated oxidative stress as shown by SOD, GSH, MDA and NO levels. SIGNIFICANCE: We can conclude that in addition to its antioxidant power, quercetin blocked Notch, Hedgehog, regulated the apoptotic and proliferative pathways and inhibited CK2α in HCC.


Assuntos
Antioxidantes/farmacologia , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo
15.
Int J Oncol ; 55(6): 1339-1348, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638201

RESUMO

The use of carbon ion therapy for cancer treatment is becoming more widespread due to the advantages of carbon ions compared with X­rays. Breast cancer patients may benefit from these advantages, as the surrounding healthy tissues receive a lower dose, and the increased biological effectiveness of carbon ions can better control radioresistant cancer cells. Accumulating evidence indicates that the Hedgehog (Hh) pathway is linked to the development and progression of breast cancer, as well as to resistance to X­irradiation and the migratory capacity of cancer cells. Hence, there is an increasing interest in targeting the Hh pathway in combination with radiotherapy. Several studies have already investigated this treatment strategy with conventional radiotherapy. However, to the best of our knowledge, the combination of Hh inhibitors with particle therapy has not yet been explored. The aim of the present study was to investigate the potential of the Hh inhibitor GANT61 as an effective modulator of radiosensitivity and migration potential in MCF­7 breast cancer cells, and compare potential differences between carbon ion irradiation and X­ray exposure. Although Hh targeting was not able to radiosensitise cells to any radiation type used, the combination of GANT61 with X­rays or carbon ions (energy: 95 MeV/n; linear energy transfer: 73 keV/µm) was more effective in decreasing MCF­7 cell migration compared with either radiation type alone. Gene expression of the Hh pathway was affected to different degrees in response to X­ray and carbon ion irradiation, as well as in response to the combination of GANT61 with irradiation. In conclusion, combining Hh inhibition with radiation (X­rays or carbon ions) more effectively decreased breast cancer cell migration compared with radiation treatment alone.


Assuntos
Neoplasias da Mama/terapia , Quimiorradioterapia/métodos , Proteínas Hedgehog/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células , Sobrevivência Celular , Perfilação da Expressão Gênica , Radioterapia com Íons Pesados/métodos , Proteínas Hedgehog/metabolismo , Humanos , Células MCF-7 , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Terapia por Raios X/métodos
16.
BMJ Case Rep ; 12(10)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585957

RESUMO

We report a case of a 60-year-old man who was a former cigar smoker with a slow-growing, large exophytic left shoulder mass (15 cm in diameter) and later found to have left axillary lymphadenopathy. Fine needle aspirate biopsy of the left shoulder mass revealed squamous cell carcinoma (SCC). However, pathology of the enlarged left axillary lymph node was reported as metastatic adenocarcinoma. The patient underwent surgical resection of the shoulder mass which comprised of SCC (>95%) and adenoid basal cell carcinoma (BCC) as a second component of the tumour. The BCC had identical histology as the metastatic carcinoma in the left axillary lymph node. Therefore, diagnosis was revised as cutaneous collision tumour with metastatic BCC. Six months later following adjuvant radiation therapy, the patient was diagnosed with metastatic BCC in the right lung. Stereotactic body radiation therapy (SBRT) and a selective hedgehog pathway inhibitor vismodegib were given with only limited efficacy. Clinical trial registration number NCT03132636.


Assuntos
Carcinoma Basocelular/secundário , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/secundário , Linfonodos/patologia , Neoplasias Cutâneas/cirurgia , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Axila/patologia , Carcinoma Basocelular/patologia , Carcinoma Basocelular/radioterapia , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/cirurgia , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Radiocirurgia/métodos , Radioterapia Adjuvante/métodos , Neoplasias Cutâneas/patologia , Resultado do Tratamento
17.
Rinsho Ketsueki ; 60(7): 843-846, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391375

RESUMO

Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and organ development. Its aberrant activation is involved in many types of cancers and is required for the maintenance of patients with leukemic stem cell (LSC). Clinical phase trials of SMO (a positive regulator in the Hh signaling pathway) inhibitors are currently underway in hematologic malignancies, such as acute myeloid leukemia (AML).


Assuntos
Biomarcadores Tumorais , Proteínas Hedgehog/fisiologia , Leucemia Mieloide Aguda/diagnóstico , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , Leucemia Mieloide Aguda/terapia , Transdução de Sinais
18.
Fitoterapia ; 137: 104281, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381957

RESUMO

Veratrum californicum is a rich source of steroidal alkaloids, many of which have proven to be antagonists of the Hedgehog (Hh) signaling pathway that becomes aberrant in over twenty types of cancer. These alkaloids first became known in the 1950's due to their teratogenic properties, which resulted in newborn and fetal lambs developing cyclopia as a result of pregnant ewes consuming Veratrum californicum. It was discovered that the alkaloids in V. californicum were concentrated in the root and rhizome of the plant with much lower amounts of the most active alkaloid, cyclopamine, present in the aerial plant, especially in the late growth season. Inspired by the limitations in analytical instrumentation and methods available to researchers at the time of the original investigation, we have used state-of-the-art instrumentation and modern analytical methods to quantitate four steroidal alkaloids based on study parameters including plant part, harvest location, and growth stage. The results of the current inquiry detail differences in alkaloid composition based on the study parameters, provide a detailed assessment for alkaloids that have been characterized previously (cyclopamine, veratramine, muldamine and isorubijervine), and identify at least six alkaloids that have not been previously characterized. This study provides insight into optimal harvest time, plant growth stage, harvest location, and plant part required to isolate, yet to be characterized, alkaloids of interest for exploration as Hh pathway antagonists with desirable medicinal properties.


Assuntos
Alcaloides/química , Esteroides/química , Veratrum/química , Alcaloides/isolamento & purificação , Proteínas Hedgehog/antagonistas & inibidores , Idaho , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Componentes Aéreos da Planta/química , Rizoma/química , Estações do Ano , Esteroides/isolamento & purificação , Alcaloides de Veratrum
19.
Gene ; 712: 143959, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278964

RESUMO

Blockade of Hedgehog signaling can prevent osteoarthritis (OA) syndromes. However, the amelioration of related inflammation condition is limited. The purpose of this study was to observe the effect of combined use of Hedgehog signaling inhibitor GANT-61 and common clinical anti-inflammatory drug indomethacin on cartilage injury and inflammation in experimental OA mice. We found that GANT-61 and indomethacin synergistically attenuate cartilage damage and serum levels of inflammatory cytokines TNF-α, IL-2 and IL-6 in OA mice. Moreover, in vitro treatment of GANT-61 and indomethacin synergistically reduced the mRNA expression of TNF-α, IL-2 and IL-6 in lipopolysaccharide (LPS)-stimulated C28/I2 chondrocytes. Mechasnistic studies showed that GANT-61 and indomethacin synergistically attenuate the expressions of cell pyroptosis-related genes caspase-1, IL-1ß and IL-18 at mRNA and protein level. To conclude, our study showed that GANT-61 and indomethacin had a synergistically ameliorating effect on osteoarthritis by mediating chondrocytes pyroptosis.


Assuntos
Cartilagem/efeitos dos fármacos , Condrócitos/citologia , Proteínas Hedgehog/antagonistas & inibidores , Indometacina/farmacologia , Osteoartrite/tratamento farmacológico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Cartilagem/patologia , Caspase 1/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piroptose , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
20.
Target Oncol ; 14(3): 253-267, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31243642

RESUMO

Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Proteínas Hedgehog/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Carcinoma Basocelular/metabolismo , Humanos , Neoplasias Cutâneas/metabolismo
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