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1.
Int J Radiat Oncol Biol Phys ; 106(3): 564-570, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678634

RESUMO

PURPOSE: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. METHODS AND MATERIALS: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. RESULTS: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. CONCLUSIONS: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.


Assuntos
Cetuximab/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Radiossensibilizantes/administração & dosagem , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Tiazóis/administração & dosagem , Adulto , Idoso , Quimiorradioterapia/métodos , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismo , Tiazóis/efeitos adversos
2.
Br J Radiol ; 93(1106): 20190742, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778316

RESUMO

OBJECTIVE: One of the major issues in current radiotherapy (RT) is the normal tissue toxicity. A smart combination of agents within the tumor would allow lowering the RT dose required while minimizing the damage to healthy tissue surrounding the tumor. We chose gold nanoparticles (GNPs) and docetaxel (DTX) as our choice of two radiosensitizing agents. They have a different mechanism of action which could lead to a synergistic effect. Our first goal was to assess the variation in GNP uptake, distribution, and retention in the presence of DTX. Our second goal was to assess the therapeutic results of the triple combination, RT/GNPs/DTX. METHODS: We used HeLa and MDA-MB-231 cells for our study. Cells were incubated with GNPs (0.2 nM) in the absence and presence of DTX (50 nM) for 24 h to determine uptake, distribution, and retention of NPs. For RT experiments, treated cells were given a 2 Gy dose of 6 MV photons using a linear accelerator. RESULTS: Concurrent treatment of DTX and GNPs resulted in over 85% retention of GNPs in tumor cells. DTX treatment also forced GNPs to be closer to the most important target, the nucleus, resulting in a decrease in cell survival and increase in DNA damage with the triple combination of RT/ GNPs/DTX vs RT/DTX. Our experimental therapeutic results were supported by Monte Carlo simulations. CONCLUSION: The ability to not only trap GNPs at clinically feasible doses but also to retain them within the cells could lead to meaningful fractionated treatments in future combined cancer therapy. Furthermore, the suggested triple combination of RT/GNPs/DTX may allow lowering the RT dose to spare surrounding healthy tissue. ADVANCES IN KNOWLEDGE: This is the first study to show intracellular GNP transport disruption by DTX, and its advantage in radiosensitization.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas , Radiossensibilizantes/farmacologia , Antineoplásicos/farmacocinética , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Docetaxel/farmacocinética , Sinergismo Farmacológico , Feminino , Ouro/farmacocinética , Células HeLa , Humanos , Radiossensibilizantes/farmacocinética , Neoplasias de Mama Triplo Negativas/radioterapia , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/radioterapia
3.
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
4.
Br J Radiol ; 93(1106): 20180781, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860336

RESUMO

OBJECTIVE: The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the predictive value of image-based factors for outcome in locally advanced head and neck cancers treated with chemoradiation. METHODS: In the week prior to the treatment [18F]-2-flu-2-deoxy-D-glucose (FDG), [18F]-3'-flu-3'deoxythymidine (FLT) and [18F]-flumisonidazole (FMISO) imaging was performed. FLT scans were repeated at 14 and 28 Gy and FMISO at 36 Gy. Overall survival, disease-free survival and local control were correlated with subvolume parameters, and with tumour-to-muscle ratio for FMISO. For every tracer, total metabolic tumour volume was calculated. RESULTS: 33 patients were included. No correlation was found between pre-treatment maximum standardised uptake value for FDG, FLT, FMISO and outcomes. Tumour volume measured on initial CT scans and initial FLT volume correlated with disease-free survivall (p = 0.007 and 0.04 respectively). FDG and FLT metabolic tumour volumes correlated significantly with local control (p = 0.005 and 0.02 respectively). In multivariate Cox analysis only individual initial TMRmax correlated with overall survival. CONCLUSION: PET/CT imaging is a promising tool. However, various aspects of image analysis need further clinical validation in larger multicentre study employing uniform imaging protocol and standardisation, especially for hypoxia tracer. ADVANCES IN KNOWLEDGE: Monitoring of biological features of the tumour using multitracer PET modality seems to be a feasible option in daily clinical practice.Evaluation of hypoxic subvolumes is more patient dependent; thus, exploration of individual parameters of hypoxia is needed. tumour-to-muscle ratio seems to be the most promising so far.


Assuntos
Quimiorradioterapia/métodos , Neoplasias de Cabeça e Pescoço/terapia , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/metabolismo , Cisplatino/administração & dosagem , Didesoxinucleosídeos/metabolismo , Intervalo Livre de Doença , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Misonidazol/análogos & derivados , Misonidazol/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Radiossensibilizantes/metabolismo , Resultado do Tratamento , Hipóxia Tumoral/efeitos dos fármacos
5.
Anticancer Res ; 39(12): 6661-6671, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810931

RESUMO

BACKGROUND: Boron neutron capture therapy (BNCT) selectively kills tumor cells while sparing adjacent normal cells. Boric acid (BA)-mediated BNCT showed therapeutic efficacy in treating hepatocellular carcinoma (HCC) in vivo. However, DNA damage and corresponding responses induced by BA-mediated BNCT remained unclear. This study aimed to investigate whether BA-mediated BNCT induced DNA double-strand breaks (DSBs) and to explore DNA damage responses in vitro. MATERIALS AND METHODS: Huh7 Human HCC cells were treated with BA and irradiated with neutrons during BA-BNCT. Cell survival and DNA DSBs were examined by clonogenic assay and expression of phosphorylated H2A histone family member X (γH2AX), respectively. The DNA damage response was explored by determining the expression levels of DNA repair- and apoptosis-associated proteins and conducting a cell-cycle analysis. RESULTS: DNA DSBs induced by BA-mediated BNCT were primarily repaired through the homologous recombination pathway. BA-mediated BNCT induced G2/M arrest and apoptosis in HCC. CONCLUSION: Our findings may enable the identification of radiosensitizers or adjuvant drugs for potentiating the therapeutic effectiveness of BA-mediated BNCT for HCC.


Assuntos
Ácidos Bóricos/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Carcinoma Hepatocelular/radioterapia , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Neoplasias Hepáticas/radioterapia , Radiossensibilizantes/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Ácidos Bóricos/farmacocinética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , Histonas/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Radiossensibilizantes/farmacocinética , Reparo de DNA por Recombinação
6.
Int J Nanomedicine ; 14: 9483-9496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819445

RESUMO

Background: The efficacy of radiotherapy for glioma is often limited by the radioresistance of glioma cells. The radiosensitizing effects of silver nanoparticles (AgNPs) on glioma were found in the previous studies of our group. In order to enhance the radiosensitivity of tumor cells and selectively kill them while reducing the side effects of irradiation therapy, targeted modification of AgNPs is urgently needed. Materials and methods: In the present study, AgNPs functionalized with polyethylene glycol (PEG) and aptamer As1411 (AsNPs) were synthesized and subsequently characterized by transmission electron microscopy, ultraviolet-visible spectroscopy and Fourier transform infrared spectroscopy. Then the targeting property of AsNPs was evaluated by dark-field imaging, confocal microscopy and in vivo imaging. Both colony formation assay and glioma-bearing mouse model were employed to study the radiosensitizing effect of AsNPs. Results: The characterization results revealed a spherical shape of AgNPs with an average diameter of 18 nm and the successful construction of AsNPs. AsNPs were confirmed to specifically target C6 glioma cells, but not normal human microvascular endothelial cells. Moreover, AsNPs could not only internalize into tumor cells, but also penetrate into the core of tumor spheroids. In vitro experiments showed that AsNPs exhibited a better radiosensitizing effect than AgNPs and PEGylated AgNPs (PNPs), inducing a higher rate of apoptotic cell death. In vivo imaging demonstrated that Cy5-AsNPs preferentially accumulated at the tumor site, and the ratio of fluorescence intensity of Cy5-AsNPs to that of Cy5-PNPs reached the maximum at 6 h post-systemic administration. Furthermore, the combination of AsNPs with irradiation significantly prolonged the median survival time of C6 glioma-bearing mice. Conclusion: Our results indicated that AsNPs could be an effective nano-radiosensitizer for glioma targeting treatment.


Assuntos
Aptâmeros de Nucleotídeos/química , Glioma/radioterapia , Nanopartículas Metálicas/química , Oligodesoxirribonucleotídeos/química , Polietilenoglicóis/química , Radiossensibilizantes/farmacologia , Prata/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Feminino , Glioma/tratamento farmacológico , Humanos , Hidrodinâmica , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Ratos , Esferoides Celulares/patologia , Eletricidade Estática , Distribuição Tecidual
8.
Enzymes ; 46: 113-127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727273

RESUMO

In radiotherapy, tumor hypoxia is the main factor responsible for treatment resistance, and the development of radiosensitizers that can overcome this is imperative. However, many drugs that are effective in vitro and in vivo fail in clinical trials, and thus it is necessary to develop an animal model that can be used for the correct evaluation of pharmacokinetics and activity. Developing chicken eggs are commonly used in various research fields such as anticancer drug sensitivity tests and cardiotoxicity tests. We examined whether the radiosensitizing activity of etanidazole, as a hypoxic cell radiosensitizer, could be evaluated using tumor-bearing chick embryo. Following the transplantation of mouse mammary carcinoma EMT6 cells on day 11, a solid tumor was formed on day 15 and an evaluation of the time-course of the tumor revealed that the tumor weight was the highest on day 18. The maximum dose of etanidazole that did not affect tumor growth and fetal survival was 1.0mg and the maximum X-ray dose was 8Gy. Etanidazole was intravenously administered 10min prior to single dose X-ray irradiation. A significant tumor growth inhibitory effect was confirmed with 1.0mg of etanidazole in combination with 8Gy X-ray. In the case of mouse colon cancer colon26 cells, the combination of 3.0mg of etanidazole and 2Gy X-ray showed 2.79 times higher radiosensitizing activity than that observed for the control group. These results demonstrate that it is possible to evaluate the activity of radiosensitizers using tumor-bearing chick embryo.


Assuntos
Neoplasias da Mama/patologia , Avaliação Pré-Clínica de Medicamentos , Etanidazol/farmacologia , Radiossensibilizantes/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Embrião de Galinha , Camundongos , Raios X
9.
Int J Nanomedicine ; 14: 7933-7946, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686819

RESUMO

Background: Human trials combining external radiotherapy (RT) and metallic nanoparticles are currently underway in cancer patients. For internal RT, in which a radioisotope such as radioiodine is systemically administered into patients, there is also a need for enhancing treatment efficacy, decreasing radiation-induced side effects and overcoming radio-resistance. However, if strategies vectorising radioiodine through nanocarriers have been documented, sensitizing the neoplasm through the use of nanotherapeutics easily translatable to the clinic in combination with the standard systemic radioiodine treatment has not been assessed yet. Method and materials: The present study explored the potential of hybrid poly(methacrylic acid)-grafted gold nanoparticles to improve the performances of systemic 131I-mediated RT on cancer cells and in tumor-bearing mice. Such nanoparticles were chosen based on their ability previously described by our group to safely withstand irradiation doses while exhibiting good biocompatibility and enhanced cellular uptake. Results: In vitro clonogenic assays performed on melanoma and colorectal cancer cells showed that poly(methacrylic acid)-grafted gold nanoparticles (PMAA-AuNPs) could efficiently lead to a marked tumor cell mortality when combined to a low activity of radioiodine, which alone appeared to be essentially ineffective on tumor cells. In vivo, tumor enrichment with PMAA-AuNPs significantly enhanced the killing potential of a systemic radioiodine treatment. Conclusion: This is the first report of a simple and reliable nanomedicine-based approach to reduce the dose of radioiodine required to reach curability. In addition, these results open up novel perspectives for using high-Z metallic NPs in additional molecular radiation therapy demonstrating heterogeneous dose distributions.


Assuntos
Ouro/química , Radioisótopos do Iodo/uso terapêutico , Nanopartículas Metálicas/química , Polímeros/química , Animais , Morte Celular , Linhagem Celular Tumoral , Feminino , Humanos , Melanoma Experimental/radioterapia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Ácidos Polimetacrílicos/química , Radiossensibilizantes/farmacologia , Dosagem Radioterapêutica , Simportadores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540386

RESUMO

Ultrasmall polyaminocarboxylate-coated gold nanoparticles (NPs), Au@DTDTPA and Au@TADOTAGA, that have been recently developed exhibit a promising potential for image-guided radiotherapy. In order to render the radiosensitizing effect of these gold nanoparticles even more efficient, the study of their localization in cells is required to better understand the relation between the radiosensitizing properties of the agents and their localization in cells and in tumors. To achieve this goal, post-functionalization of Au@DTDTPA nanoparticles by near-infrared (NIF) organic dyes (aminated derivative of cyanine 5, Cy5-NH2) was performed. The immobilization of organic Cy5-NH2 dyes onto the gold nanoparticles confers to these radiosensitizers fluorescence properties which can be exploited for monitoring their internalization in cancerous cells, for determining their localization in cells by fluorescence microscopy (a common and powerful imaging tool in biology), and for following up on their accumulation in tumors after intravenous injection.


Assuntos
Carbocianinas/análise , Corantes Fluorescentes/análise , Ouro/análise , Nanopartículas Metálicas/análise , Neoplasias/diagnóstico por imagem , Radiossensibilizantes/análise , Animais , Carbocianinas/administração & dosagem , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/administração & dosagem , Ouro/administração & dosagem , Humanos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Poliaminas/análise , Radiossensibilizantes/administração & dosagem
11.
Artif Cells Nanomed Biotechnol ; 47(1): 3832-3838, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556316

RESUMO

High atomic number Z, nanoparticles are able to enhance the photoelectric and Compton effects under X-Ray irradiation resulting the increase of radiation therapy efficacy. To achieve enhanced radiation therapy, Bi2S3 biocompatible particles coated with bovine serum albumin (BSA) (Bi2S3@BSA HNPs) were prepared through a BSA-mediated biomineralization procedure under green conditions. Then, to achieve improved chemo-radiation therapy against HT-29 cancer cells, curcumin (CUR) as natural anti-cancer therapy agent loaded on the Bi2S3@BSA (Bi2S3@BSA@CUR HNPs). Next, this synthesized nanodrug was evaluated for physical and chemical properties and in vitro cytotoxicity studies. Here, in vitro enhanced chemo-radiation combination therapy power was evaluated against HT-29 cell line under 2 Gy and 6 Gy X-ray irradiation doses. The Bi2S3@BSA HNPs without irradiation rarely affect cell viability which shown the non-toxicity of Bi2S3@BSA HNPs. The result of this study proved that Bi2S3@BSA@CUR HNPs can be used as both proficient vehicles for effective delivery of CUR and radiosensitizer in the treatment of cancer. In addition, the result of this study confirmed that the combination of high Z-element nanoradiosensitizer, Bi2S3@BSA HNPs, with a natural anti-cancer drug, CUR, enhanced therapeutic power against HT-29 cells.


Assuntos
Bismuto/farmacologia , Quimiorradioterapia , Minerais/química , Soroalbumina Bovina/química , Sulfetos/síntese química , Sulfetos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Bismuto/química , Bovinos , Técnicas de Química Sintética , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Curcumina/química , Curcumina/farmacologia , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Química Verde , Células HT29 , Humanos , Nanopartículas/química , Tamanho da Partícula , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Sulfetos/química
12.
Analyst ; 144(21): 6352-6364, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31560361

RESUMO

The inclusion of nanoparticles (NP) in radiotherapy has been shown to increase the damaging effect on tumor cells. However, the mechanisms of action of NP combined with radiotherapy, and the influence of NP parameters and cell type on their radiosensitization capability at molecular and cellular levels still remain unclear. Gold NP (AuNP) have become particularly popular due to their multiple advantages. Within this context, our research work aimed to study the biochemical radiosensitization capacity of F98 and U87-MG glioma cell lines to 1.9 nm AuNP combined with X-ray irradiation. For this purpose, synchrotron-based infrared microspectroscopy (SR-FTIRM) was used as a powerful tool for biochemical composition and treatment response assessment of cells at a single-cell level. SR-FTIRM data, supported by multivariate analysis, revealed clear AuNP-induced changes in the DNA, protein and lipid spectral regions. The AuNP-related biochemical alterations appear prior to the irradiation, which gave us a first indication on the AuNP radiosensitization action. Biochemical modifications induced by the AuNP in the presence of radiotherapy irradiations include enhanced conformational changes in the protein secondary structures, variations in the intensity and position in the phosphodiester bands, and changes in the CH2 and CH3 stretching modes. These changes are better manifested at 24 hours post-irradiation time. SR-FTIRM results showed a clear heterogeneity in the biochemical cell response, probably due to the distinct cell-NP interactions and thus, to different DNA damage and cell death processes.


Assuntos
Glioma/metabolismo , Nanopartículas Metálicas/química , Radiossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , Ouro/química , Ouro/efeitos da radiação , Humanos , Nanopartículas Metálicas/efeitos da radiação , Análise de Componente Principal , Proteínas/metabolismo , Radiossensibilizantes/química , Radiossensibilizantes/efeitos da radiação , Ratos , Espectrofotometria Infravermelho , Síncrotrons , Raios X
13.
Int J Mol Sci ; 20(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31480532

RESUMO

Gold nanoparticles (GNPs) are promising radiosensitizers with the potential to enhance radiotherapy. Experiments have shown GNP enhancement of proton therapy and indicated that chemical damage by reactive species plays a major role. Simulations of the distribution and yield of reactive species from 10 ps to 1 µs produced by a single GNP, two GNPs in proximity and a GNP cluster irradiated with a proton beam were performed using the Geant4 Monte Carlo toolkit. It was found that the reactive species distribution at 1 µs extended a few hundred nm from a GNP and that the largest enhancement occurred over 50 nm from the nanoparticle. Additionally, the yield for two GNPs in proximity and a GNP cluster was reduced by up to 17% and 60% respectively from increased absorption. The extended range of action from the diffusion of the reactive species may enable simulations to model GNP enhanced proton therapy. The high levels of absorption for a large GNP cluster suggest that smaller clusters and diffuse GNP distributions maximize the total radiolysis yield within a cell. However, this must be balanced against the high local yields near a cluster particularly if the cluster is located adjacent to a biological target.


Assuntos
Ouro , Nanopartículas Metálicas/uso terapêutico , Modelos Biológicos , Terapia com Prótons , Animais , Humanos , Nanopartículas Metálicas/química , Método de Monte Carlo , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radiossensibilizantes/uso terapêutico
14.
Food Chem Toxicol ; 133: 110807, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494133

RESUMO

Ionizing radiation (IR) resistance and toxicity to normal cells are the main problems in radiotherapy for cancer. In this study, we demonstrated that epigallocatechin gallate (EGCG) could inhibit effectively IR-induced damage to mouse normal hepatic cells AML-12, and improve dramatically the radiosensitivity of mouse hepatoma cells H22 to 60Coγ. In addition, the different effects of EGCG and underlying molecular mechanisms based on microRNA-34a (miR-34a) and apoptosis-related proteins were investigated by cells viability analysis, quantitative realtime PCR (qRT-PCR), Western blot and cells transfection. The results indicated EGCG played the key role of radiosensitization on H22 cells by activating the miR-34a/Sirt1/p53 signaling pathway. Besides, EGCG could down-regulate the expression of anti-apoptotic protein Bcl-2, and up-regulate the expression of pro-apoptotic proteins Bax and Caspase-3 in H22 cells. Interestingly, EGCG showed contrary results on AML-12 cells. Therefore, radiation protection and radiosensitization of EGCG were associated with apoptosis regulated by miR-34a/Sirt1/p53 signaling pathway.


Assuntos
Catequina/análogos & derivados , Protetores contra Radiação/farmacologia , Radiossensibilizantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Radioisótopos de Cobalto , Regulação para Baixo/efeitos dos fármacos , Raios gama , Camundongos , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Int J Radiat Biol ; 95(12): 1597-1612, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31490091

RESUMO

Background and purpose: Poly(ADP-ribose)polymerase-1 (PARP1) and DNA-dependent protein kinase (DNA-PK) play key roles in the repair of radiation-induced DNA double strand breaks, but it is unclear which is the preferred therapeutic target in radiotherapy. Here we compare small molecule inhibitors of both as radiosensitizers of head and neck squamous cell carcinoma (HNSCC) cell lines.Methods: Two PARP1 inhibitors (olaparib, veliparib) and two DNA-PK inhibitors (KU57788, IC87361) were tested in 14 HNSCC cell lines and two non-tumorigenic lines (HEK-293 and WI-38/Va-13), with drug exposure for 6 or 24 h post-irradiation, using regrowth assays. For three lines (UT-SCC-54C, -74B, -76B), radiosensitization was also assessed by clonogenic assay under oxia and acute (6 h) anoxia, and for 54C cells under chronic hypoxia (0.2% O2 for 48 h). Relationships between sensitizer enhancement ratios (SER) and gene expression, assessed by RNA sequencing, were evaluated.Results: The inhibitors were minimally cytotoxic in the absence of radiation, with 74B and 54C cells the most sensitive to both olaparib and KU57788. Median SER values for each inhibitor at 1.1 µM were 1.12 (range 1.02-1.24) for olaparib, 1.08 (1.04-1.13) for veliparib, 1.35 (1.10-1.64) for IC87361 and 1.77 (1.41-2.38) for KU57788. The higher SER values for the DNA-PK inhibitors were observed with all cell lines (except HEK-293) and all concentrations tested and were confirmed by clonogenic assay. Radiosensitization by the DNA-PK inhibitors correlated with expression of SLFN11 mRNA. Radiosensitization by IC87361 and olaparib was significantly enhanced under acute anoxia and chronic hypoxia.Conclusions: The DNA-PK inhibitors KU57788 and IC87361 are more effective radiosensitizers than the PARP-1 inhibitors olaparib and veliparib at non-cytotoxic concentrations in HNSCC cell cultures and their activity is enhanced by SLFN11 and hypoxia.


Assuntos
Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fatores de Tempo
16.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470638

RESUMO

Despite significant advances in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Chemoradiation therapy is a rational approach that has already proven beneficial for several malignancies. However, the existence of toxicity to normal tissue is a serious limitation of this treatment modality. The aim of the present study is to investigate the ability of polar steroids from starfish Patiria (=Asterina) pectinifera to enhance the efficacy of radiation therapy in colorectal carcinoma cells. The cytotoxic activity of polar steroids and X-ray radiation against DLD-1, HCT 116, and HT-29 cells was determined by an MTS assay. The effect of compounds, X-ray, and their combination on colony formation was studied using the soft agar method. The molecular mechanism of the radiosensitizing activity of asterosaponin P1 was elucidated by western blotting and the DNA comet assay. Polar steroids inhibited colony formation in the tested cells, and to a greater extent in HT-29 cells. Asterosaponin P1 enhanced the efficacy of radiation and, as a result, reduced the number and size of the colonies of colorectal cancer cells. The radiosensitizing activity of asterosaponin P1 was realized by apoptosis induction through the regulation of anti- and pro-apoptotic protein expression followed by caspase activation and DNA degradation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/genética , Asterina/química , Regulação Neoplásica da Expressão Gênica , Compostos Policíclicos/farmacologia , Radiossensibilizantes/farmacologia , Saponinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Células HCT116 , Células HT29 , Humanos , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação , Radiossensibilizantes/química , Radiossensibilizantes/isolamento & purificação , Saponinas/química , Saponinas/isolamento & purificação , Ensaio Tumoral de Célula-Tronco , Raios X , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
17.
Cancer Radiother ; 23(8): 917-921, 2019 Dec.
Artigo em Francês | MEDLINE | ID: mdl-31540838

RESUMO

Nanomedicine has undergone significant development since the 2000s and it is only very recently that two metallic nanoparticles have emerged in clinical trials. The mechanism of these radiosensitizing agents is based on the presence of atoms with a high atomic number (Z) allowing a higher dose deposition into the tumor during irradiation. The first nanoparticle used in humans is NBTXR3, composed of hafnium (Z=79), with intratumor injection for the treatment of sarcoma. Another gadolinium-based nanoparticle (Z=64), AGuIX, has been used for intravenous injection in the treatment of brain metastases. The preliminary results are promising in terms of feasibility, safety and efficacy, as evidenced by the significant number of ongoing clinical trials. The upcoming challenges for the development of nanoparticles will be the targeting of cancer cells, their biodistribution into the body, their eventual toxicity and their industrial production. In the coming years, modalities of administration and optimal combinations with radiotherapy should be defined in connection with fundamental research.


Assuntos
Nanomedicina , Nanopartículas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adenocarcinoma/radioterapia , Adenocarcinoma/secundário , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Ensaios Clínicos Fase I como Assunto , Gadolínio/uso terapêutico , Ouro/uso terapêutico , Háfnio/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Nanopartículas/efeitos adversos , Radiossensibilizantes/efeitos adversos , Sarcoma/radioterapia
18.
Anticancer Res ; 39(9): 4805-4810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519582

RESUMO

BACKGROUND/AIM: Ro 90-7501 has been reported as an inhibitor of the amyloid ß42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. MATERIALS AND METHODS: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. RESULTS: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. CONCLUSION: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.


Assuntos
Aminas/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzimidazóis/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo
19.
Nat Commun ; 10(1): 4057, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492849

RESUMO

Simultaneous imaging and treatment of infections remains a major challenge, with most current approaches being effective against only one specific group of bacteria or not being useful for diagnosis. Here we develop multifunctional nanoagents that can potentially be used for imaging and treatment of infections caused by diverse bacterial pathogens. The nanoagents are made of fluorescent silicon nanoparticles (SiNPs) functionalized with a glucose polymer (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose]) and loaded with chlorin e6 (Ce6). They are rapidly internalized into Gram-negative and Gram-positive bacteria by a mechanism dependent on an ATP-binding cassette (ABC) transporter pathway. The nanoagents can be used for imaging bacteria by tracking the green fluorescence of SiNPs and the red fluorescence of Ce6, allowing in vivo detection of as few as 105 colony-forming units. The nanoagents exhibit in vivo photodynamic antibacterial efficiencies of 98% against Staphylococcus aureus and 96% against Pseudomonas aeruginosa under 660 nm irradiation.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fotoquimioterapia/métodos , Antibacterianos/química , Antibacterianos/farmacocinética , Infecções Bacterianas/microbiologia , Dissacarídeos/química , Bactérias Gram-Negativas/fisiologia , Bactérias Gram-Positivas/fisiologia , Humanos , Nanopartículas/química , Porfirinas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Radiossensibilizantes/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
20.
Cancer Invest ; 37(9): 489-500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496302

RESUMO

Prostate cancer is the most common cancer and leading cause of cancer death for males. Imipramine (IMI), which is a tricyclic antidepressant, has also been shown to has antineoplastic effect. This study was performed to investigate the radiosensitizing effect of IMI on DU145 prostate cancer cell. Cells were divided into 4 groups. Cell index, apoptotic activity, cell cycle arrest, oxidative stress and EAG1 channel currents were determined in all groups. Our findings showed that combined treatment with IMI and radiotherapy (RAD) did not enhance radiosensitivity of DU145 cells but as unexpected finding, treatment of IMI alone was more effective in DU145 cells.


Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Imipramina/farmacologia , Neoplasias da Próstata/metabolismo , Radiossensibilizantes/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Neoplasias da Próstata/terapia , Radioterapia
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