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1.
Adv Exp Med Biol ; 1232: 155-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893406

RESUMO

The success of treatment for malignancies, especially those undergoing radiation therapy or chemotherapy, has long been recognized to depend on the degree of hypoxia in the tumor. In addition to the prognostic value of knowing the tumor's initial level of hypoxia, assessing the tumor oxygenation during standard therapy or oxygen-related treatments (such as breathing oxygen-enriched gas mixtures or taking drugs that can increase oxygen supply to tissues) can provide valuable data to improve the efficacy of treatments. A series of early clinical studies of tumors in humans are ongoing at Dartmouth and Emory using electron paramagnetic resonance (EPR) oximetry to assess tumor oxygenation, initially and over time during either natural disease progression or treatment. This approach has the potential for reaching the long-sought goal of enhancing the effectiveness of cancer therapy. In order to effectively reach this goal, we consider the validity of the practical and statistical assumptions when interpreting the measurements made in vivo for patients undergoing treatment for cancer.


Assuntos
Neoplasias , Oximetria , Oxigênio , Hipóxia Tumoral , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Neoplasias/metabolismo , Oxigênio/metabolismo
2.
Adv Exp Med Biol ; 1232: 169-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893407

RESUMO

Inhospitable conditions within the tumor microenvironment (TME) are a characteristic feature ('hallmark') of most solid malignancies. Regional tumor hypoxia is a primary deficiency since it plays a key role in malignant progression. Severe hypoxia is often associated with other detrimental conditions in the TME as a consequence of hypoxia-/HIF-1α-induced (with/without oncogene-direction and/or reciprocal interaction of cancer cells with TME cells) metabolic re-programming, exorbitant extracellular adenosine (ADO) generation and VEGF overexpression/VEGF-R activation. Re-programming of the tumor metabolism inter alia includes a 'selfish' upregulation of aerobic glycolysis/glycolytic flux ('Warburg effect'), a strongly enhanced glutaminolysis in tumor cells, ketogenesis in cancer-associated fibroblasts, and an acceleration of the tryptophan uptake/intensified catabolism yielding kynurenine, which can support the malignant phenotype. Aerobic glycolysis and glutaminolysis result in lactate accumulation (up to 40 mM), and together with the enhanced ketogenesis and CO2/carbonic acid production lead to extracellular acidosis (pHe < 6.8). These traits of the TME individually or collectively operate towards cancer progression via e.g. promotion of genetic instability and mutation, resistance to apoptosis, clonal selection, limitless cell survival and sustained proliferation, continuous angiogenesis and tumor growth, local invasion and distant metastasis, anti-tumor immunosuppression and resistance to therapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias , Hipóxia Tumoral , Microambiente Tumoral , Linhagem Celular Tumoral , Progressão da Doença , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/fisiopatologia , Fenótipo
3.
Adv Exp Med Biol ; 1232: 177-182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893408

RESUMO

Tumor hypoxia may play a fundamental role in determining the radiotherapy outcome for several cancer types. Functional imaging with hypoxia specific radiotracers offers a way to visualize and quantify regions of increased radioresistance, which may benefit from dose escalation strategies. Conversion of the uptake in positron emission tomography (PET) images into oxygenation maps offers a way to quantitatively characterize the microenvironment. However, normalization of the uptake with respect to a well-oxygenated reference volume (WOV), which should be properly selected, is necessary when using conversion functions. This study aims at assessing the sensitivity of quantifying tumor oxygenation based on 18F-fluoromisonidazole (FMISO) PET with respect to the choice of the location and the oxygenation level of the WOV in head and neck cancer patients. WOVs varying not only in shape and location but also with respect to the assigned pO2 level were considered. pO2 values other than the standard 60 mmHg were selected according to the specific tissue type included in the volume. For comparison, the volume which would be considered as hypoxic based on a tissue-to-muscle ratio equal to 1.4 was also delineated, as conventionally done in clinical practice. Hypoxia mapping strategies are found highly sensitive to selection of the location of well-oxygenated region, but also on its assigned oxygenation level, which is crucial for hypoxia-guided adaptive dose escalation strategies.


Assuntos
Neoplasias de Cabeça e Pescoço , Oximetria/instrumentação , Oximetria/normas , Oxigênio , Tomografia por Emissão de Pósitrons , Hipóxia Tumoral , Neoplasias de Cabeça e Pescoço/fisiopatologia , Humanos , Misonidazol/análogos & derivados , Misonidazol/metabolismo , Oxigênio/metabolismo , Microambiente Tumoral
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
6.
Cancer Res ; 79(18): 4577-4579, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31519775

RESUMO

Understanding the way hypoxia influences tumor biology is important; to study tumor hypoxia, simple and robust quantification of tissue oxygenation levels in vivo is necessary. Real-time noninvasive imaging without the use of expensive large equipment (PET or MRI) is most desirable. Photoacoustic imaging, in the form of volumetric multispectral optoacoustic tomography, as described in this issue of Cancer Research, paves the way for tumor hypoxia studies using an intrinsic optical contrast agent (hemoglobin), up to cm depth and 0.1-mm spatial resolution, in real-time 3D. This approach may find use in the clinic to assess tumor status and therapeutic efficacy.See related article by Ron et al., p. 4767.


Assuntos
Neoplasias , Técnicas Fotoacústicas , Meios de Contraste , Humanos , Hipóxia , Hipóxia Tumoral
7.
Phys Med ; 64: 145-156, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31515013

RESUMO

AIM: The negative impact of tumour hypoxia on cancer treatment outcome has been long-known, yet there has been little success combating it. This paper investigates the potential role of in silico modelling to help test emerging hypoxia-targeting treatments in cancer therapy. METHODS: A Medline search was undertaken on the current landscape of in silico models that simulate cancer therapy and evaluate their ability to test hypoxia-targeting treatments. Techniques and treatments to combat tumour hypoxia and their current challenges are also presented. RESULTS: Hypoxia-targeting treatments include tumour reoxygenation, hypoxic cell radiosensitization with nitroimidazoles, hypoxia-activated prodrugs and molecular targeting. Their main challenges are toxicity and not achieving adequate delivery to hypoxic regions of the tumour. There is promising research toward combining two or more of these techniques. Different types of in silico therapy models have been developed ranging from temporal to spatial and from stochastic to deterministic models. Numerous models have compared the effectiveness of different radiotherapy fractionation schedules for controlling hypoxic tumours. Similarly, models could help identify and optimize new treatments for overcoming hypoxia that utilize novel hypoxia-targeting technology. CONCLUSION: Current therapy models should attempt to incorporate more sophisticated modelling of tumour angiogenesis/vasculature and vessel perfusion in order to become more useful for testing hypoxia-targeting treatments, which typically rely upon the tumour vasculature for delivery of additional oxygen, (pro)drugs and nanoparticles.


Assuntos
Simulação por Computador , Neoplasias/patologia , Neoplasias/terapia , Hipóxia Tumoral , Humanos , Modelos Biológicos
8.
Int J Radiat Biol ; 95(12): 1708-1717, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31545117

RESUMO

Purpose: To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells.Materials and methods: B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a 10B-carrier (L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated.Results: BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a 10B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT.Conclusion: BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.


Assuntos
Terapia por Captura de Nêutron de Boro , Hipertermia Induzida , Neoplasias Pulmonares/secundário , Melanoma/patologia , Tirapazamina/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Melanoma/tratamento farmacológico , Melanoma/radioterapia , Camundongos , Tirapazamina/administração & dosagem , Tirapazamina/uso terapêutico , Resultado do Tratamento
9.
Mater Sci Eng C Mater Biol Appl ; 104: 109979, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500001

RESUMO

The efficacy of photodynamic therapy (PDT) is reduced in the context of hypoxic environments. This is problematic, considering that hypoxia is exhibited in the vast majority of malignant tumors. Thus, increasing the concentration of oxygen in malignant tumors improves PDT treatment outcomes. Studies show that MnO2 nanoparticles can produce oxygen when it reacts with endogenous H2O2. Herein, we encapsulated Protoporphyrin IX (PPIX) in the liposome bilayer (PPIX-Lipo), which was then coated with MnO2 nanoparticles to construct PPIX-Lipo-MnO2 (PPIX-Lipo-M) in order to enhance PDT efficacy under tumor hypoxia. The PDT results show that PPIX-Lipo-M was more cytotoxic to breast cancer cells than PPIX-Lipo while under hypoxic conditions, indicating that the production of oxygen gas in hypoxic conditions improved treatment outcomes. Upon encapsulating PPIX into the liposome, the aqueous solubility of PPIX significantly improved. Consequently, the cellular uptake of both PPIX-Lipo and PPIX-Lipo-M also increased significantly compared to that of bare PPIX. Overall, PPIX-Lipo-M has the capacity to act as a therapeutic agent that relieves hypoxia and hence improve PDT efficacy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Lipossomos/química , Compostos de Manganês/química , Óxidos/química , Protoporfirinas/química , Protoporfirinas/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Peróxido de Hidrogênio/farmacologia , Células MCF-7 , Nanopartículas/química , Oxigênio/química , Fotoquimioterapia/métodos
10.
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
11.
Chem Commun (Camb) ; 55(72): 10792-10795, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31432816

RESUMO

Hypoxia, as an important feature in tumor sites, greatly hinders the performance of photosensitizers, thus affecting the efficacy of photodynamic therapy (PDT). Therefore, designing and preparing new photosensitizer with high photosensitivity under hypoxic condition presents a great challenge that urgently needs to be solved. In this work, a new nano-MOF material using Mn(ii) as the active center can catalytically decompose high concentrations of H2O2 in tumor cells to generate O2, thereby improving the PDT efficacy in hypoxic tumors. The Mn-MOF also produces 1O2 under light irradiation, which finally induces cancer cell apoptosis. This work offers a new strategy for the design and discovery of effective photosensitizers for PDT.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Manganês/farmacologia , Estruturas Metalorgânicas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Peróxido de Hidrogênio/metabolismo , Manganês/química , Estruturas Metalorgânicas/química , Camundongos , Oxigênio/metabolismo , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Propriedades de Superfície
12.
Biomed Res Int ; 2019: 9749751, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467922

RESUMO

Gastric cancer (GC) is a common tumor-associated lethal disease, and invasiveness and metastasis are primary challenges in its clinical treatment. Hypoxia microenvironment cannot be ignored in the process of metastasis. Hypoxia inducible factor-1α (HIF-1α) is the core component of the hypoxia signaling pathway. The aim of this study was to identify potential hub genes and signaling pathways associated with HIF-1α. We explored the invasiveness- and metastasis-associated phenotype of GC via bioinformatics analysis and molecular studies. Differentially expressed genes (DEGs) were identified in GC cells and HIF-1α-knockdown GC cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and a protein-protein interaction (PPI) network was constructed. Hub genes were identified via centrality analysis and Molecular Complex Detection (MCODE) module analysis. The findings suggested that prolyl 4-hydroxylase beta polypeptide (P4HB) has strong associations with HIF-1α. Further, we observed that HIF-1α and P4HB were upregulated in SGC-7901 and BGC-823 cells. In addition, inhibition of HIF-1α expression reduced invasion and metastasis in GC cells; this effect was partially reversed by P4HB overexpression. Our results confirm that P4HB plays a significant role in the regulatory network of HIF-1α. Therefore, HIF-1α and P4HB may be considered potential biomarkers of GC.


Assuntos
Carcinogênese/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Isomerases de Dissulfetos de Proteínas/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Hipóxia Tumoral/genética , Microambiente Tumoral/genética
13.
Int J Mol Sci ; 20(17)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461993

RESUMO

Cancer cell phenotype largely depends on oxygen availability. The atmospheric oxygen concentration (21%) used in in vitro studies is much higher than in any human tissue. Using well-characterized patient-derived melanoma cell lines, we compared: (i) activities of several signaling pathways, and (ii) the effects of vemurafenib and trametinib in hyperoxia (21% O2), normoxia (6% O2) and hypoxia (1% O2). A high plasticity of melanoma cells in response to changes in oxygen supplementation and drug treatment was observed, and the transcriptional reprograming and phenotypic changes varied between cell lines. Normoxia enhanced the expression of vascular endothelial growth factor (VEGF), glucose metabolism/transport-related genes, and changed percentages of NGFR- and MITF-positive cells in cell line-dependent manner. Increased protein stability might be responsible for high PGC1α level in MITFlow melanoma cells. Vemurafenib and trametinib while targeting the activity of MAPK/ERK pathway irrespective of oxygen concentration, were less effective in normoxia than hyperoxia in reducing levels of VEGF, PGC1α, SLC7A11 and Ki-67-positive cells in cell line-dependent manner. In conclusion, in vitro studies performed in atmospheric oxygen concentration provide different information on melanoma cell phenotype and response to drugs than performed in normoxia, which might partially explain the discrepancies between results obtained in vitro and in clinical settings.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma/metabolismo , Oxigênio/metabolismo , Hipóxia Tumoral , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Transcrição Associado à Microftalmia/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vemurafenib/farmacologia
14.
Opt Lett ; 44(15): 3773-3776, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31368965

RESUMO

Hypoxia, a low tissue oxygenation condition caused by insufficient oxygen supply, leads to potentially irreversible tissue damage, such as brain infarction during stroke. Intravascular oxygenation has long been used by photoacoustic imaging, among other imaging modalities, to study hypoxia. However, intravascular oxygenation describes only the oxygen supply via microcirculation, which does not directly reflect the amount of free oxygen available for metabolism in the interstitial fluid. Therefore, to fully understand hypoxia, it is highly desirable to monitor blood oxygenation as well as tissue oxygenation during the same biological process. In this work, by combining high-resolution photoacoustic microscopy (PAM) and a novel bioreducible N-oxide-based hypoxia-sensitive probe HyP-650, we have demonstrated simultaneous imaging of intravascular oxygenation and tissue hypoxia. We have established detailed chemical, optical, and photoacoustic properties of HyP-650 for hypoxic activation in vitro and in living cells. We have also performed PAM on hindlimb ischemia models and tumor-bearing mice to study the correlation between intravascular oxygenation and tissue oxygenation at various hypoxic levels. We expect that Hyp-650 enhanced photoacoustic imaging will find a variety of applications in brain and cancer research.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Oxigênio/metabolismo , Técnicas Fotoacústicas/métodos , Animais , Membro Posterior/irrigação sanguínea , Isquemia/metabolismo , Isquemia/patologia , Camundongos , Microscopia , Hipóxia Tumoral
15.
Yonsei Med J ; 60(8): 727-734, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347327

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC) is a common cancer worldwide. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA (lncRNA), has been reported to be aberrantly expressed in hypoxic cancer cells. MALAT1 plays a significant role in many malignancies, including HCC. The aim of this study was to explore the role of MALAT1 in hypoxic HCC cells and its underlying regulatory mechanism. MATERIALS AND METHODS: Quantitative reverse transcription PCR (qRT-PCR) assay was performed to detect the mRNA levels of MALAT1 and microRNA-200a (miR-200a) in HCC cells. Cell invasion and migration ability were evaluated by Transwell assay. Starbase v2.0 and luciferase reporter assay were employed to identify the association between MALAT1 and miR-200a. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. RESULTS: MALAT1 levels were significantly upregulated in HCC cells under hypoxia. Hypoxia promoted proliferation, migration, and invasion, and blocked apoptosis in Hep3B cells, which were weakened by knockdown of MALAT1. Starbase v2.0 showed that MALAT1 and miR-200a have a complementarity region, and luciferase reporter assay verified that MALAT1 interacted with miR-200a in Hep3B cells. Moreover, MALAT1 negatively regulated the expression of miR-200a. miR-200a levels were dramatically downregulated in HCC cells under hypoxia. Upregulation of miR-200a inhibited proliferation, migration, and invasion, and induced apoptosis in Hep3B cells under hypoxia. Interestingly, downregulation of miR-200a partially reversed the tumor-suppressive effect of knockdown of MALAT1 on Hep3B cells in hypoxic condition. CONCLUSION: LncRNA MALAT1 was involved in proliferation, migration, invasion, and apoptosis by interacting with miR-200a in hypoxic Hep3B cells, revealing a new mechanism of MALAT1 involved in hypoxic HCC progression.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Hipóxia Tumoral/genética , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica , RNA Longo não Codificante/genética , Regulação para Cima/genética
16.
Int J Radiat Oncol Biol Phys ; 105(3): 548-558, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271827

RESUMO

PURPOSE: Human papillomavirus negative (HPV-ve) head and neck squamous cell carcinoma (HNSCC) has a poor prognosis compared with HPV+ve HNSCCs. Expression of p16 in HPV+ve HNSCC is thought to mediate radiosensitivity via inhibition of cyclin-dependent kinase (CDK) 4/6. We used a clinically approved CDK4/CDK6 inhibitor, palbociclib, and assessed its effect on radiosensitivity in HNSCC. METHODS AND MATERIALS: The effect of palbociclib on radiosensitivity was determined in HPV-ve and HPV+ve HNSCC cell lines using colony survival assays, immunofluorescent staining of repair proteins, homologous recombination assays, cell cycle, and metaphase spread analyses. RESULTS: Only HPV-ve HNSCC cells were radiosensitized by palbociclib, which also occurred at hypoxic levels associated with radioresistance. Palbociclib led to decreased induction of BRCA1 and RAD51 after irradiation. Homologous recombination was diminished and repair of radiation-induced DNA damage was delayed in the presence of palbociclib, leading to increased chromosomal damage. Failure to repair radiation-induced damage led to cell death as a result of mitotic catastrophe. CONCLUSIONS: Here, we highlight a therapeutic strategy to improve the radiosensitivity of HPV-ve HNSCC, a patient group that has an unmet and urgent need for improved radiation therapy efficacy.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/radioterapia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Tolerância a Radiação , Radiossensibilizantes/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Proteína BRCA1/metabolismo , Ciclo Celular , Morte Celular , Linhagem Celular Tumoral , Aberrações Cromossômicas/induzido quimicamente , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Recombinação Homóloga , Humanos , Proteínas de Neoplasias/metabolismo , Papillomaviridae , Fosforilação , Rad51 Recombinase/metabolismo , Proteína do Retinoblastoma/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Hipóxia Tumoral , Ensaio Tumoral de Célula-Tronco
17.
Mol Med Rep ; 20(2): 1893-1900, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257503

RESUMO

Mutations of isocitrate dehydrogenase (IDH) 1 and 2 occur in low­grade gliomas, acute myeloid leukemias and other types of solid cancer. By catalyzing the reversible conversion between isocitrate and α­ketoglutarate (α­KG), IDH1 and 2 contribute to the central process of metabolism, including oxidative and reductive metabolism. IDH1 and 2 mutations result in the loss of normal catalytic function and acquire neomorphic activity, facilitating the conversion of α­KG into an oncometabolite, (R)­2­hydroxyglutarate, which can cause epigenetic modifications and tumorigenesis. Small­molecule inhibitors of mutant IDH1 and 2 have been developed, and ongoing clinical trials have shown promising results in hematological malignancies, but not in gliomas. These previous findings make it necessary to identify the mechanism and develop more effective therapies for IDH1­mutant gliomas. In the present study, it was demonstrated that under hypoxic conditions, patient­derived primary glioma cells and HCT116 cells, both of which carry a monoallelic IDH1 arginine 132 to histidine mutation (R132H), have a slower growth rate than the corresponding wild­type IDH1 cells. Western blot analysis showed that IDH1 R132H­mutant cancer cells exhibited upregulated IDH2 protein expression under hypoxic conditions. Furthermore, the silencing of IDH2 using small interfering RNA significantly inhibited the growth of IDH1­mutant cells under hypoxic conditions. Finally, [U­13C5]glutamine tracer analysis showed that IDH2 knockdown reduced the reductive carboxylation of α­KG into isocitrate in HCT116R132H/+ cells under hypoxic conditions. The present study showed for the first time, to the best of our knowledge, that IDH2 plays a compensatory role in maintaining reductive carboxylation­dependent lipogenesis and proliferation in IDH1 R132H tumor cells. Therefore, IDH2 could serve as a potential anti­tumor target for IDH1­mutant tumors, which may provide a new strategy for treatment.


Assuntos
Carcinogênese/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Sobrevivência Celular/genética , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Células HCT116 , Humanos , Isocitratos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Mutação/genética , Hipóxia Tumoral/genética
18.
Br J Radiol ; 92(1104): 20190373, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31356111

RESUMO

OBJECTIVE: To investigate the association between multiparametric MRI (mpMRI) imaging features and hypoxia-related genetic profiles in prostate cancer. METHODS: In vivo mpMRI was acquired from six patients prior to radical prostatectomy. Sequences included T2 weighted (T2W) imaging, diffusion-weighted imaging, dynamic contrast enhanced MRI and blood oxygen-level dependent imaging. Imaging data were co-registered with histology using three-dimensional deformable registration methods. Texture features were extracted from T2W images and parametric maps from functional MRI. Full transcriptome genetic profiles were obtained using next generation sequencing from the prostate specimens. Pearson correlation coefficients were calculated between mpMRI data and hypoxia-related gene expression levels. Results were validated using glucose transporter one immunohistochemistry (IHC). RESULTS: Correlation analysis identified 34 candidate imaging features (six from the mpMRI data and 28 from T2W texture features). The IHC validation showed that 16 out of the 28 T2W texture features achieved weak but significant correlations (p < 0.05). CONCLUSIONS: Weak associations between mpMRI features and hypoxia gene expressions were found. This indicates the potential use of MRI in assessing hypoxia status in prostate cancer. Further validation is required due to the low correlation levels. ADVANCES IN KNOWLEDGE: This is a pilot study using radiogenomics approaches to address hypoxia within the prostate, which provides an opportunity for hypoxia-guided selective treatment techniques.


Assuntos
Neoplasias da Próstata/diagnóstico por imagem , Hipóxia Tumoral/genética , Idoso , Imagem de Difusão por Ressonância Magnética , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
19.
Int J Nanomedicine ; 14: 3705-3722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190820

RESUMO

Hypoxia is a hallmark of malignant tumors and often correlates with increasing tumor aggressiveness and poor treatment outcomes. Therefore, early diagnosis and effective killing of hypoxic tumor cells are crucial for successful tumor control. There has been a surge of interdisciplinary research aimed at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. These mainly include hypoxia-active nanoparticles, anti-hypoxia agents, and agents that target biomarkers of tumor hypoxia. Hypoxia-active nanoparticles have been intensively investigated and have demonstrated advanced effects on targeting tumor hypoxia. In this review, we present an overview of the reports published to date on hypoxia-activated prodrugs and their nanoparticle forms used in tumor-targeted therapy. Hypoxia-responsive nanoparticles are inactive during blood circulation and normal physiological conditions but are activated by hypoxia once they extravasate into the hypoxic tumor microenvironment. Their use can enhance the efficiency of tumor chemotherapy, radiotherapy, fluorescence and photoacoustic intensity, and other imaging and therapeutic strategies. By targeting the broad habitats of tumors, rather than tumor-specific receptors, this strategy has the potential to overcome the problem of tumor heterogeneity and could be used to design diagnostic and therapeutic nanoparticles for a broad range of solid tumors.


Assuntos
Nanopartículas/química , Nanomedicina Teranóstica , Hipóxia Tumoral , Diagnóstico por Imagem , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/tratamento farmacológico
20.
Radiat Res ; 192(2): 159-168, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31188068

RESUMO

In this work, we investigated the change in tumor microenvironment caused by semi-ablative high-dose irradiation and its implication on tumor cell survival, reoxygenation of hypoxic cells and repopulation in FSaII tumors grown subcutaneously in the hind legs of C3H mice. Tumors were exposed to 10-30 Gy of X-ray radiation in a single exposure, and the vascularity and blood perfusion were assessed based on the levels of CD31 expression and Hoechst 33342 perfusion, respectively. The tumor hypoxia was assessed by staining for pimonidazole adduct formation and the expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9). Tumor cell survival was determined using in vivo-in vitro excision assay method. The proportion of hypoxic cells in the tumor was determined from the surviving cell fraction in tumors exposed to a test dose under aerobic and hypoxic conditions. Radiation expsoure markedly reduced the functional vascularity and blood perfusion, and profoundly increased the expression of HIF-1α and CA9 pointing to an increase in tumor hypoxia. The overall clonogenic cell survival progressively decreased during 2-5 days postirradiation, most likely due to the radiation-induced vascular dysfunction. In turn, the proportion of surviving hypoxic cells decreased over several days postirradiation, presumably due to reoxygenation of hypoxic cells. The oxygen supplied through small fractions of blood vessels that survived the high-dose exposure, together with a reduction of oxygen consumption due to massive cell death, appeared to be the cause of the reoxygenation of hypoxic cells. The surviving tumor cells then subsequently repopulated. The findings from this study using a murine tumor model suggest that the efficacy of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) may be significantly improved by allowing an inter-fraction time for reoxygenation while avoiding repopulation.


Assuntos
Fibrossarcoma/patologia , Fibrossarcoma/radioterapia , Oxigênio/metabolismo , Hipofracionamento da Dose de Radiação , Animais , Vasos Sanguíneos/efeitos da radiação , Morte Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Fibrossarcoma/metabolismo , Camundongos , Hipóxia Tumoral/efeitos da radiação , Microambiente Tumoral/efeitos da radiação
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