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1.
Nucleic Acids Res ; 48(16): 9109-9123, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32729622

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR-CHK1-CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Fator 2 Relacionado a NF-E2/genética , Reparo de DNA por Recombinação/genética , Células A549 , Animais , Proteína Quinase CDC2/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quinase 1 do Ponto de Checagem/genética , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Técnicas de Inativação de Genes , Xenoenxertos , Humanos , Camundongos , Quassinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Reparo de DNA por Recombinação/efeitos dos fármacos , Reparo de DNA por Recombinação/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos
2.
Cancer Immunol Immunother ; 69(10): 2075-2088, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32447411

RESUMO

In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma targeted radionuclide therapy (TRT), we explore the interplay between immune system and the melanin ligand [131I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [131I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [131I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [131I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [131I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [131I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p < 0.0001) compared to TRT alone. Specifically, [131I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26 days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/métodos , Radioisótopos do Iodo/uso terapêutico , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Tolerância a Radiação/efeitos dos fármacos , Animais , Terapia Combinada , Melanoma Experimental/patologia , Camundongos , Células Tumorais Cultivadas
3.
Cancer Res ; 80(12): 2651-2662, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32291318

RESUMO

Ceramide-induced endothelial cell apoptosis boosts intestinal stem cell radiosensitivity. However, the molecular connection between these two cellular compartments has not been clearly elucidated. Here we report that ceramide and its related enzyme acid sphingomyelinase (ASM) are secreted by irradiated endothelial cells and act as bystander factors to enhance the radiotoxicity of intestinal epithelium. Ceramide and the two isoforms of ASM were acutely secreted in the blood serum of wild-type mice after 15 Gy radiation dose, inducing a gastrointestinal syndrome. Interestingly, serum ceramide was not enhanced in irradiated ASMKO mice, which are unable to develop intestinal failure injury. Because ASM/ceramide were secreted by primary endothelial cells, their contribution was studied in intestinal epithelium dysfunction using coculture of primary endothelial cells and intestinal T84 cells. Adding exogenous ASM or ceramide enhanced epithelial cell growth arrest and death. Conversely, blocking their secretion by endothelial cells using genetic, pharmacologic, or immunologic approaches abolished intestinal T84 cell radiosensitivity. Use of enteroid models revealed ASM and ceramide-mediated deleterious mode-of-action: when ceramide reduced the number of intestinal crypt-forming enteroids without affecting their structure, ASM induced a significant decrease of enteroid growth without affecting their number. Identification of specific and different roles for ceramide and ASM secreted by irradiated endothelial cells opens new perspectives in the understanding of intestinal epithelial dysfunction after radiation and defines a new class of potential therapeutic radiomitigators. SIGNIFICANCE: This study identifies secreted ASM and ceramide as paracrine factors enhancing intestinal epithelial dysfunction, revealing a previously unknown class of mediators of radiosensitivity.


Assuntos
Ceramidas/metabolismo , Células Endoteliais/metabolismo , Mucosa Intestinal/patologia , Lesões por Radiação/patologia , Esfingomielina Fosfodiesterase/metabolismo , Animais , Efeito Espectador/efeitos da radiação , Células Cultivadas , Ceramidas/sangue , Técnicas de Cocultura , Desipramina/farmacologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/efeitos da radiação , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Masculino , Camundongos , Camundongos Knockout , Comunicação Parácrina/genética , Comunicação Parácrina/efeitos da radiação , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Lesões por Radiação/sangue , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielina Fosfodiesterase/sangue , Esfingomielina Fosfodiesterase/genética
4.
PLoS One ; 15(3): e0229272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119704

RESUMO

BACKGROUND AND AIMS: Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. METHODS: NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. RESULTS: The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. CONCLUSIONS: Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação , Regulação para Cima , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Proteínas de Neoplasias/antagonistas & inibidores , Peptídeos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais , Ubiquitinação , Regulação para Cima/efeitos dos fármacos , Receptor fas/metabolismo
5.
Cancer Immunol Res ; 8(4): 451-464, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127391

RESUMO

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiotherapy in colorectal cancer. We used human and mouse colorectal cancer cell lines, organoids, mouse syngeneic colorectal cancer tumor graft models, and colorectal cancer tissues from patients who received radiotherapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation induced IDO1 overexpression in colorectal cancer through type I and II IFN signaling. IDO1 enzymatic activity directly influenced colorectal cancer radiation sensitivity. IDO1 inhibition sensitized colorectal cancer to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side effects. These data demonstrated that IDO1 inhibition potentiates radiotherapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.


Assuntos
Neoplasias Colorretais/radioterapia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Interferons/farmacologia , Oximas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Sulfonamidas/farmacologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Mucosa Intestinal/efeitos da radiação , Cinurenina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Protetores contra Radiação/farmacologia
6.
Oxid Med Cell Longev ; 2020: 2167129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190169

RESUMO

Although the mitochondrial antiviral signaling protein (MAVS), located in the mitochondrial outmembrane, is believed to be a signaling adaptor with antiviral feature firstly, it has been shown that suppression of MAVS enhanced radioresistance. The mechanisms underlying this radioresistance remain unclear. Our current study demonstrated that knockdown of MAVS alleviated the radiation-induced mitochondrial dysfunction (mitochondrial membrane potential disruption and ATP production), downregulated the expressions of proapoptotic proteins, and reduced the generation of ROS in cells after irradiation. Furthermore, inhibition of mitochondrial ROS by the mitochondria-targeted antioxidant MitoQ reduced amounts of oligomerized MAVS after irradiation compared with the control group and also prevented the incidence of MN and increased the survival fraction of normal A549 cells after irradiation. To our knowledge, it is the first report to indicate that MAVS, an innate immune signaling molecule, is involved in radiation response via its oligomerization mediated by radiation-induced ROS, which may be a potential target for the precise radiotherapy or radioprotection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Multimerização Proteica , Tolerância a Radiação , Espécies Reativas de Oxigênio/metabolismo , Trifosfato de Adenosina/biossíntese , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Humanos , Interferons/metabolismo , Interleucina-6/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Modelos Biológicos , Compostos Organofosforados/farmacologia , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Raios X
7.
Ecotoxicol Environ Saf ; 192: 110261, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32018153

RESUMO

The Chlorella vulgaris has been generally recognized as a promising microalgal model to study stress-related responses due to its ability to withstand against ionizing and non-ionizing radiation. The objective of the present study was to investigate the effect of CaCl2 pre-treatment at different concentrations on the responses of microalga C. vulgaris under gamma radiation toxicity. Changes in growth, physiological parameters and biochemical compositions of the algae pretreated with 0.17 (normal), 5, and 10 mM CaCl2 were analyzed under 300 Gy gamma irradiation and compared to those of gamma-free control. The results showed that parameters including specific growth rate, cell size, chlorophyll and protein contents, ascorbate peroxidase (APX), and superoxide dismutase (SOD) activity, Ferric Reducing Antioxidant Power (FRAP), and the ratios of nucleic acid to protein negatively affected by gamma irradiation. All these parameters, except for the ratios of nucleic acid to protein significantly increased in the algae when pretreated with a CaCl2 content higher than normal concentration. The analysis also showed that parameters including catalase activity, proline, and carotenoid content, the level of lipid peroxidation, and electrolyte leakage (EL) significantly increased under gamma irradiation but not affected significantly under different CaCl2 pre-treatments. Additionally, specific growth rate, chlorophyll a and protein content, APX and SOD activity, FRAP, lipid peroxidation, electrolyte leakage, and the ratios of nucleic acid to protein were the only parameters that significantly affected by the interaction of gamma toxicity and CaCl2 pretreatment. Overall, the results suggested that regardless of the CaCl2 effect, the algal cells responded to gamma radiation more efficiently by increasing proline, carotenoids content, and CAT activity. More important, it was concluded that calcium had an essential role in modifying the detrimental effect of gamma toxicity on the algae mainly by increasing the activity of ascorbate peroxidase and superoxide dismutase and maintaining the reducing antioxidant power (FRAP) of the cells at a high level.


Assuntos
Cloreto de Cálcio/farmacologia , Chlorella vulgaris/efeitos da radiação , Raios gama/efeitos adversos , Tolerância a Radiação/efeitos dos fármacos , Antioxidantes/metabolismo , Ascorbato Peroxidases/metabolismo , Carotenoides/metabolismo , Catalase/metabolismo , Chlorella vulgaris/efeitos dos fármacos , Chlorella vulgaris/crescimento & desenvolvimento , Chlorella vulgaris/metabolismo , Clorofila/metabolismo , Clorofila A/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Microalgas/efeitos dos fármacos , Microalgas/crescimento & desenvolvimento , Microalgas/metabolismo , Microalgas/efeitos da radiação , Prolina/metabolismo , Superóxido Dismutase/metabolismo
8.
Mol Med Rep ; 21(3): 1501-1508, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016459

RESUMO

Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide. It is also the second most common cause of cancer­associated mortality; it accounted for about 9.2% of all cancer deaths in 2018, most of which were due to resistance to therapy. The main treatment for CRC is surgery, generally associated with chemotherapy, radiation therapy and combination therapy. However, while chemo­radiotherapy kills differentiated cancer cells, mesenchymal stem­like cells are resistant to this treatment, and this can give rise to therapy­resistant tumors. Our previous study isolated T88 primary colon cancer cells from a patient with sporadic colon cancer. These cells exhibited mesenchymal and epithelial features, high levels of epithelial­to­mesenchymal transition transcription factors, and stemness markers. In addition, it was revealed that lithium chloride (LiCl), a specific glycogen synthase kinase (GSK)­3ß inhibitor, induced both the mesenchymal­to­epithelial transition and differentiation, and also reduced cell migration, stemness features and cell plasticity in these primary colon cancer cells. The aim of the present study was to investigate the effect of LiCl treatment on the viability of primary colon cancer cells exposed to 7 Gy delivered by high­energy photon beams, which corresponds to 6 megavolts of energy. To achieve this aim, the viability of irradiated T88 cells was compared with that of irradiated T88 cells pre­treated with LiCl. As expected, it was observed that LiCl sensitized primary colon cancer cells to high­energy photon irradiation treatment. Notably, the decrease in cell viability was greater with combined therapy than with irradiation alone. To explore the molecular basis of this response, the effect of LiCl on the expression of Bax, p53 and Survivin, which are proteins involved in the apoptotic mechanism and in death escape, was analyzed. The present study revealed that LiCl upregulated the expression of pro­apoptotic proteins and downregulated the expression of proteins involved in survival. These effects were enhanced by high­energy photon irradiation, suggesting that LiCl could be used to sensitize colon cancer cells to radiation therapy.


Assuntos
Cloreto de Lítio/farmacologia , Fótons , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/radioterapia , Humanos , Radioterapia de Alta Energia/métodos , Transdução de Sinais/efeitos dos fármacos
9.
Nat Rev Gastroenterol Hepatol ; 17(5): 298-313, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32005946

RESUMO

Radiotherapy is used in the treatment of approximately 50% of all malignancies including gastrointestinal cancers. Radiation can be given prior to surgery (neoadjuvant radiotherapy) to shrink the tumour or after surgery to kill any remaining cancer cells. Radiotherapy aims to maximize damage to cancer cells, while minimizing damage to healthy cells. However, only 10-30% of patients with rectal cancer or oesophageal cancer have a pathological complete response to neoadjuvant chemoradiation therapy, with the rest suffering the negative consequences of toxicities and delays to surgery with no clinical benefit. Furthermore, in pancreatic cancer, neoadjuvant chemoradiation therapy results in a pathological complete response in only 4% of patients and a partial pathological response in only 31%. Resistance to radiation therapy is polymodal and associated with a number of biological alterations both within the tumour itself and in the surrounding microenvironment including the following: altered cell cycle; repopulation by cancer stem cells; hypoxia; altered management of oxidative stress; evasion of apoptosis; altered DNA damage response and enhanced DNA repair; inflammation; and altered mitochondrial function and cellular energetics. Radiosensitizers are needed to improve treatment response to radiation, which will directly influence patient outcomes in gastrointestinal cancers. This article reviews the literature to identify strategies - including DNA-targeting agents, antimetabolic agents, antiangiogenics and novel immunotherapies - being used to enhance radiosensitivity in gastrointestinal cancers according to the hallmarks of cancer. Evidence from radiosensitizers from in vitro and in vivo models is documented and the action of radiosensitizers through clinical trial data is assessed.


Assuntos
Neoplasias Gastrointestinais/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Antineoplásicos/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Humanos , Telômero/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
10.
Radiat Res ; 193(3): 286-300, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32017668

RESUMO

New radiosensitizers are urgently needed for radiation therapy patients with localized hepatocellular carcinoma (HCC) that is refractory to radical surgery. We previously found that genistein, a major soy isoflavone, exerts radioprotective effects on L-02 normal liver cells at low concentrations. Here, we report that 5 µM genistein shows less harm to L-02 cells than HCC cells and that it significantly enhances the radiosensitivity of HCC cells by enhancing DNA damage, chromosomal aberrations and cell cycle arrest at G2/M phase and by exacerbating apoptosis. Mechanistically, genistein aggravates X-ray-induced decreases in the levels of phospho-Bad (Ser136) but enhances the levels of phospho-Chk2 (Thr68), phospho-ATM (Ser1981) and γ-H2AX. Micro-array analysis indicated that downregulation of POU6F and CCNE2 expression and upregulation of FBXO32 and cyclin B1 expression might play vital roles in genistein-induced radiosensitivity. These findings suggest genistein as an interesting candidate for adjuvant radiotherapy for HCC and indicate that genistein causes less harm to normal cells than HCC cells by inducing G2/M arrest and apoptosis.


Assuntos
Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Divisão Celular/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias Hepáticas/patologia , Tolerância a Radiação/efeitos dos fármacos , Animais , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Camundongos , Raios X
11.
J Exp Clin Cancer Res ; 39(1): 8, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924239

RESUMO

Low oxygen condition (hypoxia) is considered a hallmark of rapidly growing solid tumors. The presence of hypoxia renders tumor cells resistant to conventional chemo- and radio-therapy selecting a more malignant and invasive phenotype, and playing a negative role in patient prognosis. This commentary wishes to recognize the 2019 Nobel Prize in Medicine awarded to three physicians-scientists, Prof. William G. Kaelin Jr., Prof. Sir Peter J. Ratcliffe, and Prof. Gregg L. Semenza, for their discovery of the mechanisms mediating cell ability to sense and adapt to changes in oxygen availability. Their studies established the basis for our understanding of the role of hypoxia in a variety of diseases, including anemia, renal failure, cardiovascular disease, metabolic diseases, and cancer, paving the way for new promising therapeutic strategies through the development of drugs that can either activate or block the oxygen-sensing machinery.


Assuntos
Neoplasias/metabolismo , Hipóxia Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Distinções e Prêmios , Desenvolvimento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Tolerância a Radiação/efeitos dos fármacos , Hipóxia Tumoral/efeitos dos fármacos
12.
Artif Cells Nanomed Biotechnol ; 48(1): 479-487, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31975621

RESUMO

Cervical cancer is the second most common malignant tumour threatening women's health. In recent years, heavy-ion beam therapy is becoming a newly emerging therapeutic mean of cancer; however, radio-resistance and radiation-induced damage constitute the main obstacles for curative treatment of cervical cancer. Therefore, to identify the radiosensitizers is essential. Here, we investigated the effects of Wnt signalling pathway on the response of 12C6+ radiation in HeLa cells. XAV939, an inhibitor of Wnt signalling pathway, was added two hours before 12C6+ radiation.12C6+ radiation inhibited the viability of HeLa cells in a time-dependent manner, and inhibiting Wnt signalling using XAV939 significantly intensified this stress. Meanwhile, 12C6+ radiation induced a significant increased cell apoptosis, G2/M phase arrest, and the number of γ-H2AX foci. Supplementation with XAV939 significantly increased the effects induced by 12C6+ radiation alone. Combining XAV939 with 12C6+ irradiation, the expression of apoptotic genes (p53, Bax, Bcl-2) was significantly increased, while the expression of Wnt-related genes (Wnt3a, Wnt5a, ß-catenin, cyclin D1 and c-Myc) was significantly decreased. Overall, these findings suggested that blockage of the Wnt/ß-catenin pathway effectively sensitizes HeLa cells to 12C6+ irradiation, and it may be a potential therapeutic approach in terms of increasing the clinical efficacy of 12C6+ beams.


Assuntos
Apoptose , Compostos Heterocíclicos com 3 Anéis/farmacologia , Tolerância a Radiação , Neoplasias do Colo do Útero , Via de Sinalização Wnt , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/radioterapia , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/efeitos da radiação
13.
ACS Appl Mater Interfaces ; 12(4): 4231-4240, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31912727

RESUMO

Radiotherapy has been extensively used to treat cancer patients because it can effectively damage most solid tumors without penetration limits. A hypoxic microenvironment in solid tumors leads to severe radioresistance and expression of hypoxic inducible factor-1 (HIF-1), which results in poor efficacy of radiotherapy alone. Herein, we report the excellent efficacy of radiotherapy achieved using a new type of yolk-shell Cu2-xSe@PtSe (CSP) nanosensitizer functionalized with the HIF-1α inhibitor acriflavine (ACF). We prepare the CSP nanosensitizer through the interfacial redox reactions between chloroplatinic acid and Cu2-xSe nanoparticles (CS) and then functionalize the nanosensitizer with ACF through their electrostatic interactions. We show that the synthesized CSP nanosensitizer can arrest the cell cycle (i.e., at the gap 2/mitosis (G2/M) phases) of tumor cells to enhance their sensitivity to X-rays and decompose endogenous H2O2 into O2 to reduce hypoxia and increase the production of reactive oxygen species, which leads to severe damage to DNA double strands and apoptosis of tumor cells. We also show that the ACF on the surface of CSP nanoparticles can effectively reduce the expression of HIF-1α. All these effects lead to a low vascular endothelial growth factor, low density of microvessels in tumor, decreased cell proliferation, and increased cell apoptosis, which synergistically and drastically enhance the efficacy of radiotherapy. This work provides insights and guidance for developing novel nanosensitizers to enhance the efficacy of radiotherapy.


Assuntos
Acriflavina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Nanopartículas Metálicas , Proteínas de Neoplasias , Neoplasias , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes , Células 3T3 , Acriflavina/química , Acriflavina/farmacologia , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/radioterapia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Terapia por Raios X
14.
J Appl Microbiol ; 128(6): 1534-1546, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31991509

RESUMO

AIMS: The objective was to evaluate the possible synergistic effect of cranberry juice (CJ) and commercial citrus extract (BS) against FCV-F9 viral titre in vitro in combination with γ-irradiation and to determinate the D10 values and radiosensitivity increase. METHODS AND RESULTS: Virus samples were treated with a formulation containing a mixture of BS or CJ. Results showed a D10 of 0·05, 0·42% and 1·34 kGy for the virus treated with the BS, the CJ and the irradiation alone respectively. Concentrations needed to reduce 6 log TCID50  ml-1 of viral titre were BS-0·3%, CJ-2·52% and 8·04 kGy. Irradiation combined with BS-0·01% and CJ-0·1% against FCV-F9 virus showed D10 values of 0·74 and 0·72 kGy, respectively, resulting in a viral radiosensitization of 1·28 and 1·50 for respective treatments. CONCLUSION: The higher viral radiosensitization observed after combining γ-irradiation with BS-0·01% and CJ-0·1% indicates that CJ and BS could be used as antiviral agents alone or in combination with γ-irradiation to prevent NoV outbreaks. SIGNIFICANCE AND IMPACT OF THE STUDY: Cranberry juice and BS could be used in hurdle approaches in combined treatment with γ-irradiation to assure food safety without a detrimental effect on nutritional value and maintain low processing cost.


Assuntos
Antivirais/farmacologia , Calicivirus Felino/fisiologia , Irradiação de Alimentos/métodos , Raios gama , Tolerância a Radiação/efeitos dos fármacos , Calicivirus Felino/efeitos dos fármacos , Calicivirus Felino/efeitos da radiação , Citrus/química , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Inocuidade dos Alimentos , Vaccinium macrocarpon/química
15.
Biochem Biophys Res Commun ; 523(4): 947-953, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31964531

RESUMO

Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 µM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/radioterapia , Quercetina/uso terapêutico , Tolerância a Radiação/efeitos dos fármacos , Receptores Notch/metabolismo , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/efeitos da radiação , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Quercetina/farmacologia , Tolerância a Radiação/efeitos da radiação , Radiação Ionizante , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Carcinog ; 59(2): 202-214, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31793078

RESUMO

Circular RNAs (circRNAs) are involved in the regulation of gene expression in different physiological and pathological processes. These macromolecules can act as microRNA (miRNA) sponges and play an important role as gene regulators throughout the circRNA-miRNA pathway. In this study, we established a radioresistance model with the nasopharyngeal carcinoma cell line CNE-2, and then analyzed the differences in the circRNAs between radioresistant and normal nasopharyngeal carcinoma cell lines using a high-throughput microarray. Tested circRNAs included 1042 upregulated and 1558 downregulated circRNAs. Relevant signaling pathways associated with the circRNAs and their target miRNAs were analyzed using bioinformatics analysis to determine the radioresistance of the differentially expressed circRNAs. Curcumin was used to treat irradiated cell lines, and changes in the circRNA before and after curcumin treatment were analyzed to investigate the radiosensitization effects of curcumin. The results showed that curcumin could regulate the circRNA-miRNA-messenger RNA network and inhibit the epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and growth factor receptor-bound protein 2 (GRB2) to achieve radiosensitization. Thus, circRNA acted as a miRNA sponge and regulated the expression of miRNA, thereby affecting EGFR, STAT3, and GRB2 expression and radiosensitization.


Assuntos
Curcumina/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Circular/genética , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/efeitos da radiação , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação
17.
J Cancer Res Clin Oncol ; 146(3): 721-737, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31786739

RESUMO

PROPOSE: Poly (ADP-ribose) polymerase 1 inhibitors were originally investigated as anti-cancer therapeutics with BRCA1/2 genes mutation. Here, we investigate the effectiveness of a novel PARP1 inhibitor fluzoparib, for enhancing the radiation sensitivity of NSCLC cells lacking BRCA1/2 mutation. METHODS: We used MTS assays, western blotting, colony formation assays, immunofluorescence staining, and flow cytometry to evaluate the radiosensitization of NSCLC cells to fluzoparib and explore the underlying mechanisms in vitro. Through BRCA1 and RAD50 genes knockdown, we established dysfunctional homologous recombination (HR) DNA repair pathway models in NSCLC cells. We next investigated the radiosensitization effect of fluzoparib in vivo using human NSCLC xenograft models in mice. The expression of PARP1 and BRCA1 in human NSCLC tumor samples was measured by immunohistochemistry. Furthermore, we sequenced HR-related gene mutations and analyzed their frequencies in advanced NSCLC. RESULTS: In vitro experiments in NSCLC cell lines along with in vivo experiments using an NSCLC xenograft mouse model demonstrated the radiosensitization effect of fluzoparib. The underlying mechanisms involved increased apoptosis, cell-cycle arrest, enhanced irradiation-induced DNA damage, and delayed DNA-damage repair. Immunohistochemical staining showed no correlation between the expression of PARP1 and BRCA1. Moreover, our sequencing results revealed high mutation frequencies for the BRCA1/2, CHEK2, ATR, and RAD50 genes. CONCLUSION: The potential therapeutic value of fluzoparib for increasing the radiation sensitivity of NSCLC is well confirmed. Moreover, our findings of high mutation frequencies among HR genes suggest that PARP1 inhibition may be an effective treatment strategy for advanced non-small cell lung cancer patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteína BRCA1 , Proteína BRCA2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Mutação , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Radiat Res ; 193(1): 82-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31738663

RESUMO

Radiation-resistant hypoxic tumor areas continue to present a major limitation for successful tumor treatment. To overcome this radiation resistance, an oxygen-independent treatment is proposed using UVC-emitting LuPO4:Pr3+ nanoparticles (NPs) and X rays. The uptake of the NPs as well as their effect on cell proliferation was investigated on A549 lung cancer cells by using inverted time-lapse microscopy and transmission electron microscopy. Furthermore, cytotoxicity of the combined treatment of X rays and LuPO4:Pr3+ NPs was assessed under normoxic and hypoxic conditions using the colony formation assay. Transmission electron microscopy (TEM) images showed no NP uptake after 3 h, whereas after 24 h incubation an uptake of NPs was documented. LuPO4:Pr3+ NPs alone caused a concentration-independent cell growth delay within the first 60 h of incubation. The combined treatment with UVC-emitting NPs and X rays reduced the radiation resistance of hypoxic cells by a factor of two to the level of cells under normoxic condition. LuPO4:Pr3+ NPs cause an early growth delay but no cytotoxicity for the tested concentration. The combination of these NPs with X rays increases cytotoxicity of normoxic and hypoxic cancer cells. Hypoxic cells become sensitized to normoxic cell levels.


Assuntos
Nanopartículas , Tolerância a Radiação/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Raios Ultravioleta , Células A549 , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Humanos , Tolerância a Radiação/efeitos da radiação
19.
Surgery ; 167(1): 56-63, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585718

RESUMO

BACKGROUND: The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation, dedifferentiation, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5), which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression. METHODS: We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment. RESULTS: We evaluated 24 patient papillary thyroid cancer specimens; BRAFV600E mutations were identified in 18 out of 24 (75.0%); 1 patient tumor had an HRAS mutation, and the remaining 5 were BRAF and RAS wildtype. Dual treatment with dabrafenib and trametinib increased NIS expression (mean fold change 4.01 ± 2.04, P < .001), and single treatment with dabrafenib had no effect (mean fold change 0.98 ± 0.42, P = .84). Tumor samples that had above-median NIS expression increases came from younger patients (39 vs 63 years, P < .05). CONCLUSION: Dual treatment with BRAF and MEK inhibitors upregulated NIS expression, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Radioisótopos do Iodo/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Simportadores/metabolismo , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Radioisótopos do Iodo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/farmacologia , Oximas/uso terapêutico , Cultura Primária de Células , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas , Pirimidinonas , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
20.
In Vivo ; 34(1): 33-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882460

RESUMO

BACKGROUND/AIM: Radiation mitigator, GS-nitroxide, JP4-039, was evaluated for mitigation of total body irradiation (TBI) in Fanconi anemia (FA) Fancd2-/- (129/Sv), Fancg-/- (B6), and Fanca-/- (129/Sv) mice. MATERIALS AND METHODS: JP4-039 dissolved in 30% 2-hydroxypropyl-ß-cyclodextrin was injected intramuscularly 24 h after total body irradiation (9.25 Gy) into Fanca-/-, Fancd2-/- and Fancg-/- mice. Irradiation survival curves were performed in vitro using bone marrow stromal cell lines derived from Fanca-/-, Fancd2-/- and Fancg-/- mice. RESULTS: FA mice demonstrate genotype specific differences in TBI mitigation by JP4-039. Radiation effects in derived bone marrow stromal cell lines in vitro were mitigated by drugs that block apoptosis, but not necroptosis or ferroptosis. CONCLUSION: FA mouse models are valuable for elucidating DNA repair pathways in cell and tissue responses to TBI, and the role of drugs that target distinct cell death pathways.


Assuntos
Anemia de Fanconi/genética , Óxidos de Nitrogênio/farmacologia , Protetores contra Radiação/farmacologia , Irradiação Corporal Total/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Linhagem Celular , Modelos Animais de Doenças , Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Genótipo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/genética , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética
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