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1.
Anticancer Res ; 40(9): 5001-5013, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878788

RESUMO

AIM: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. MATERIALS AND METHODS: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. RESULTS: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. CONCLUSION: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Radiossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , 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 , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ácido Edético/análogos & derivados , Ácido Edético/química , Raios gama , Humanos , Concentração Inibidora 50 , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química
2.
Anticancer Res ; 40(8): 4675-4680, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727791

RESUMO

BACKGROUND: From the design and synthesis of enantiomers, we can expect to obtain two compounds with different pharmacokinetics and pharmacological activities at the same time, which is thought to lead to the development of efficient anticancer agents. Chiral-2-nitroimidazole TX-2036 derivatives exhibit stereo-configuration (R- and S-configuration)-dependent tyrosine kinase inhibitory activity, and the activity of the tyrosine kinase domain of EGF receptor (EGFR-tyk) is suppressed. In order to clarify the reason why the effects on EGFR-tyk activity differ depending on stereoisomers, we tried to analyze the interaction between each TX-2036 derivative and EGFR-tyk. MATERIALS AND METHODS: The 2-nitroimidazole-based radiosensitizer TX-2036 series were synthesized and their molecular features were examined using protein kinase inhibition assay and molecular structural analysis. RESULTS: R-configured TXs (TX-2043, -2030, and -2036) exhibited more potent protein kinase inhibitory activity than S-configured TXs (TX-2044, - 2031, and -2037), and the IC50 value of TX-2036 was 1.8 µM. CONCLUSION: R-configured TXs interacted with Lys721 and Thr766 of EGFR-tyk. The combinations of amino acid residues targeted by the S-configured TXs were different from each other (Ile765 and Thr766 (TX-2044), Ser696, Thr766, and Thr830 (TX-2031), Gly772, Cys773, and Thr830 (TX-2037)). Preparing a series of isomers with different target sites was considered beneficial when the target was mutated.


Assuntos
Domínios Proteicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Isomerismo , Radiossensibilizantes/farmacologia , Estereoisomerismo
3.
Int J Nanomedicine ; 15: 3719-3727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547024

RESUMO

Purpose: Most solid tumors contain areas of chronic hypoxia. Gold nanoparticles (GNP) have been extensively explored as enhancers of external beam radiation; however, GNP have lower cellular uptake in hypoxic conditions than under normoxic conditions. Conversely, the chelator diacetyl-bis (N(4)-methylthiosemicarbazonato) copper II (CuATSM) deposits copper in hypoxic regions, allowing for dose enhancement in previously inaccessible regions. Methods: External beam sources with different spectra were modeled using a Monte Carlo code (EGSnrc) to evaluate radioenhancement in a layered model with metal solutions. Also considered was a simple concentric layered tumor model containing a hypoxic core with each layer varying in concentrations of either copper or gold according to hypoxic conditions. Low energy external photon beams were then projected onto the tumor to determine the regional dose enhancement dependent on hypoxic conditions. Results: Dose enhancement was more pronounced for beam spectra with low energy photons (225 kVp) and was highly dependent on metal concentrations from 0.1 g/kg to 100 g/kg. Increasing the depth of the metallic solution layer from 1 cm to 6 cm decreased dose enhancement. A small increase in the dose enhancement factor (DEF) of 1.01 was predicted in the hypoxic regions of the tumor model with commonly used diagnostic concentrations of CuATSM. At threshold concentrations of toxic subcutaneous injection levels, the DEF increases to 1.02, and in simulation of a high concentration of CuATSM, the DEF increased to 1.07. High concentration treatments are also considered, as well as synergistic combinations of GNP/CuATSM treatments. Conclusion: The research presented is novel utilization of CuATSM to target hypoxic regions and act as a radiosensitizer by the nature of its ability to deposit copper metal in reduced tissue. We demonstrate CuATSM at high concentrations with low energy photons can increase dose deposition in hypoxic tumor regions.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Método de Monte Carlo , Compostos Organometálicos/farmacocinética , Fótons , Tiossemicarbazonas/farmacocinética , Hipóxia Tumoral , Relação Dose-Resposta à Radiação , Modelos Biológicos , Imagens de Fantasmas , Radiossensibilizantes/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação
4.
J Cancer Res Ther ; 16(2): 215-221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474504

RESUMO

Objective: Osteosarcoma is a malignant bone tumor and is generally treated with radiotherapy combined with radiosensitizers. The aim of the present study was to investigate the radiosensitization effects of berberine on osteosarcoma cells and the role of Rad51 in radiosensitivity by berberine. Materials and Methods: Cells from the human osteosarcoma cell line MG-63 were exposed to γ-ray irradiation (0, 2, 4, 6, and 8 Gy) and berberine (20 µM). Radiosensitivity was evaluated by determining cell viability using an MTT assay. Flow cytometry was used to determine cell cycle and apoptosis. Real-time PCR and western blot were performed to analyze the mRNA and protein expressions of Rad51. The protein levels of E-cadherin and vimentin were also measured to evaluate the epithelial-mesenchymal transition (EMT) process. Tumor invasion was determined by the Boyden chamber assay. Results: Berberine exacerbated the decline in viability of MG-63 cells exposed to γ-rays irradiation at various concentrations (25, 50, 75, and 100 µmol/L) and induced cell cycle arrest in the G2/M phase as well as apoptosis. The mRNA and protein expressions of Rad51 were significantly decreased by berberine in MG-63 cells. Inhibition of Rad51 by B02 enhanced the radiosensitivity of MG-63 cells. Berberine inhibited their invasive capability as well as increased E-cadherin and decreased vimentin protein levels; this indicated that berberine suppressed the EMT process in MG-63 cells exposed to γ-rays irradiation. Conclusion: Berberine enhances the radiosensitivity of MG-63 osteosarcoma cells. Rad51 is a potential target of berberine in the radiosensitization of osteosarcoma.


Assuntos
Berberina/farmacologia , Pontos de Checagem do Ciclo Celular , Sobrevivência Celular , Transição Epitelial-Mesenquimal , Osteossarcoma/radioterapia , Rad51 Recombinase/antagonistas & inibidores , Radiossensibilizantes/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/radioterapia , Linhagem Celular Tumoral , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Rad51 Recombinase/metabolismo
5.
Life Sci ; 256: 117974, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553924

RESUMO

The brain tumor is the abnormal growth of heterogeneous cells around the central nervous system and spinal cord. Most clinically prominent brain tumors affecting both adult and pediatric are glioblastoma, medulloblastoma, and ependymoma and they are classified according to their origin of tissue. Chemotherapy, radiotherapy, and surgery are important treatments available to date. However, these treatments fail due to multiple reasons, including chemoresistance and radiation resistance of cancer cells. Thus, there is a need of new therapeutic designs to target cell signaling and molecular events which are responsible for this resistance. Recently epigenetic changes received increased attention because it helps in understanding chromatin-mediated disease mechanism. The epigenetic modification alters chromatin structure that affects the docking site of many drugs which cause chemo-resistance of cancer therapy. This review centers the mechanism of how epigenetic changes affect the transcription repression and activation of various genes including Polycomb gene, V-Myc avian myelocytomatosis viral oncogene (MYCN). This review also put forth the pathway of radiation-induced reactive oxygen species generation and its role in epigenetic changes in the cellular level and its impact on tissue physiology. Additionally, there is a strong relationship between the behavior of an individual and environment-induced epigenetic regulation of gene expression. The review also discusses Transcriptome heterogeneity and role of tumor microenvironment in glioblastoma. Overall, this review emphasis important and novel epigenetic targets that could be of therapeutic benefit, which helps in overcoming the unsolved chromatin alteration in brain cancer.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Epigênese Genética/genética , Animais , Neoplasias Encefálicas/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/efeitos da radiação , Humanos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Transcriptoma/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiação
6.
Neoplasma ; 67(3): 576-583, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32182087

RESUMO

The standard therapy for malignant primary bone tumors such as osteosarcoma involves major surgeries. For tumors located in difficult regions such as the pelvis, surgical intervention could lead to serious side effects for example loss of a limb and/or function, loss of bowel, bladder and sexual function as well as problems with wound healing and surgical complications. Therefore, exploring other approaches that can improve or complement current surgical techniques is important. Hence, sensitizing primary bone tumors to radiation could offer an additional strategy that could complement surgery and significantly improve survival and quality of life. Gold nanoparticles (AuNPs) have been shown to enhance radiosensitivity by increasing the local dose of radiation inside tumors. Therefore, the referred procedure of preparation and functionalization of gold nanoparticles may be used for investigation whether DNA repair inhibition in the presence of AuNPs leads to an effective radiosensitizing strategy for primary bone tumor cells and explore the mechanism of how this may be happening. In our work, we prepared gold nanoparticles and verified the relation between the size of the AuNPs and their uptake in tumor 143B cells and also investigated whether the optimal size of the AuNPs should not be smaller than the size of nuclear envelope pores (20-50 nm). Hence, two different AuNPs systems were prepared: the first one with AuNPs core size of about 5 nm (BS) and the second one with AuNPs core size of about 50 nm (ZA). For cellular AuNPs uptake enhancement, we functionalized the AuNPs with signaling peptides. For this purpose we prepared PEG-coated AuNPs functionalized with signal peptides for targeted transport into the cytoplasm (CPP) and into the cell nucleus (CPP + NLS). The toxicity of the AuNPs systems was assessed by MTS assay. We prepared stable functionalized AuNPs systems of both sizes. With the functionalizing of the AuNPs using signal peptides (CPP, NLS), the AuNPs penetrated into the cell nucleus. The referred procedure of preparation and functionalization of gold nanoparticles may be used for investigating inhibition of DNA repair in the presence of AuNPs and it could lead to new understanding in overcoming radioresistance in primary bone tumor cells.


Assuntos
Portadores de Fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Nanopartículas Metálicas , Osteossarcoma , Radiossensibilizantes/farmacologia , Linhagem Celular Tumoral , Núcleo Celular , Ouro , Humanos , Transporte Proteico , Qualidade de Vida , Células Tumorais Cultivadas
7.
Sci Adv ; 6(4): eaaz1722, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010792

RESUMO

In the current clinical boron neutron capture therapy (BNCT), p-boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.


Assuntos
Compostos de Boro/farmacologia , Terapia por Captura de Nêutron de Boro , Metabolismo Energético/efeitos dos fármacos , Fenilalanina/análogos & derivados , Álcool de Polivinil/farmacologia , Radiossensibilizantes/farmacologia , Animais , Compostos de Boro/química , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Espectrometria de Massas , Camundongos , Neoplasias/terapia , Fenilalanina/química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Álcool de Polivinil/química , Álcool de Polivinil/farmacocinética , Radiossensibilizantes/química , Radiossensibilizantes/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nanoscale ; 12(9): 5587-5600, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32100776

RESUMO

As one of the most promising noninvasive therapeutic modalities, sonodynamic therapy (SDT) can focus the ultrasound energy on tumor sites located in deep tissue and locally activate the preloaded sonosensitizer to kill tumor cells. However, exploring sonosensitizers with high SDT efficacy and desirable biosafety is still a significant challenge. Herein, we utilized the hydrophilic-hydrophobic self-assembly technology to assemble the hydrophobic organic dye Ce6 and broad spectral anti-cancer agent Paclitaxel with hydrophilic organic dye IR783 to generate a nanoscale sonosensitizer, Ce6-PTX@IR783, without the introduction of extra nanomaterials into the fabrication to guarantee high therapeutic biosafety and further potential clinical translation. The constructed nanodrug was endowed with an external ultrasound-activatable chemo-sonodynamic effect and photoacoustic imaging performance via integrating multiple moieties into one nanosystem. Ce6 could enhance the sonodynamic effect, while PTX exerted a chemotherapeutic effect, and IR783 was applied to increase tumor-specific accumulation and assist in fulfilling photoacoustic imaging. In particular, the small particle size (70 nm) of Ce6-PTX@IR783 contributed to the increased tumor accumulation via the enhanced permeability and retention effect. The high synergistically chemo-sonodynamic therapeutic efficacy has been successfully demonstrated in vitro and in vivo, in addition to the demonstrated high biodegradability, biocompatibility and biosafety. This facile self-assembly procedure provides an intriguing strategy for highly efficient utilization of hydrophobic drugs and is liable to realize large-scale production and further clinical translation.


Assuntos
Antineoplásicos Fitogênicos/química , Nanopartículas/química , Paclitaxel/química , Porfirinas/química , Radiossensibilizantes/química , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Endocitose , Feminino , Corantes Fluorescentes/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Oxigênio Singlete/metabolismo , Distribuição Tecidual , Transplante Heterólogo
9.
Phys Med Biol ; 65(8): 085002, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32101796

RESUMO

High-Z nanoparticles (NP) as radio-sensitization agents provide the feasibility of dose localization within the tumor in radiotherapy. Dose enhancement of NPs in the presence of a magnetic field (MF) could be challenged when magnetic resonance imaging (MRI) systems are used as an image-guided system. The MF can influence dose enhancement of NPs at their interfaces and surrounding medium and affect their dose deposition behavior. In the TOPAS Monte Carlo code, gold nanoparticle (GNP) and superparamagnetic iron oxide nanoparticle (SPION) were irradiated using 70 and 150 MeV proton beams, in presence of transverse MF strengths with 0, 1, 3, and 7 T. The changes in the liberated secondary electrons from NPs and their dose enhancement ratio (DER), magnetic dose enhancement ratio (MDER), and angular dose distribution in 10 nm shell thicknesses up to 500 nanometers from their centers were measured. The central plane of NPs was considered as a scorer. Its thickness was 2 nm and divided into 6-degree sectors with 10 nm radial length. The dose deposition in this voxelated scorer was calculated. The values of the deposited doses around NPs decrease rapidly while the DERs resulted from the secondary electrons are increased. MDERs are changed within [Formula: see text] and [Formula: see text] for 20 and 50 nm radius NPs, respectively. The variation in the angular dose distribution around a singular NP was not considerable when different MF strengths were applied. The dose values in the voxelated central plane show very similar results for the same NPs types in the different MF strengths. The typically used MF in the MRI systems would not considerably affect the energy deposition behavior of the secondary electrons produced in the interaction of proton beam with NPs, at least in the near vicinity of NPs. The DERs of NPs in a water medium resulted from emerged secondary electrons, experience a low degree of perturbation in the presence of an MF. The results of this study show that the NPs as dose enhancement agents can also be used in an MF without pronounced modification in their efficacy.


Assuntos
Campos Magnéticos , Método de Monte Carlo , Nanopartículas , Prótons , Radiossensibilizantes/farmacologia , Elétrons , Compostos Férricos/química , Compostos Férricos/farmacologia , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas , Dosagem Radioterapêutica
10.
Nanotechnology ; 31(19): 195103, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31978912

RESUMO

The integration of chemotherapy drugs and photosensitizers to form versatile nanoplatforms for achieving chemo-photodynamic synergetic therapy has shown great superiority in tumor theranostic applications. We constructed pH-responsive nanoparticles (DOX/PB NPs) encapsulating the chemotherapeutic drug doxorubicin (DOX) into the cores of PLGA NPs coated with bovine serum albumin (BSA) via a water-in-oil (W/O/W) emulsion method. A simple and efficient chemo-photodynamic synergetic nanoplatform (DOX/PB@Ce6 NPs) was obtained by the adsorption of photosensitizer chlorin e6 (Ce6) onto the surface of the DOX/PB NPs. With optimal size, pH-responsive drug release behavior and excellent singlet oxygen production, the DOX/PB@Ce6 NPs have the potential to enhance anti-tumor efficiency. The cellular uptake, cytotoxicity, chemo-photodynamic synergetic effect and biocompatibility of the NPs were evaluated based on HeLa cells via in vitro experiments. The in vitro chemo-photodynamic synergetic experiments indicated that the DOX/PB@Ce6 NPs had remarkable cancer cell killing efficiency under laser irradiation. Notably, by hemolysis assay, all the NPs displayed excellent blood compatibility and were expected to be applicable for intravenous injection. In summary, the designed DOX/PB@Ce6 NPs multifunctional theranostic nanoplatform had excellent reactive oxygen species generation and would be a potential therapeutic platform for chemo-photodynamic synergetic therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Porfirinas/farmacologia , Radiossensibilizantes/farmacologia , Antibióticos Antineoplásicos/química , Cápsulas , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Sinergismo Farmacológico , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas , Tamanho da Partícula , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas/química , Radiossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo
11.
Int J Radiat Oncol Biol Phys ; 107(1): 212-221, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987970

RESUMO

PURPOSE: Muscle-invasive bladder cancer has a 40% to 60% 5-year survival rate with radical treatment by surgical removal of the bladder or radiation therapy-based bladder preservation techniques, including concurrent chemoradiation. Elderly patients cannot tolerate current chemoradiation therapy regimens and often receive only radiation therapy, which is less effective. We urgently need effective chemotherapy agents for use with radiation therapy combinations that are nontoxic to normal tissues and tolerated by elderly patients. METHODS AND MATERIALS: We have identified histone deacetylase (HDAC) inhibitors as promising agents to study. Pan-HDAC inhibition, using panobinostat, is a good strategy for radiosensitization, but more selective agents may be more useful radiosensitizers in a clinical setting, resulting in fewer systemic side effects. Herein, we study the HDAC class I-selective agent romidepsin, which we predict to have fewer off-target effects than panobinostat while maintaining an effective level of tumor radiosensitization. RESULTS: In vitro effects of romidepsin were assessed by clonogenic assay and showed that romidepsin was effective in the nanomolar range in different bladder cancer cells and radiosensitized these cells. The radiosensitizing effect of romidepsin was confirmed in vivo using superficial xenografts. The drug/irradiation combination treatment resulted in significant tumor growth delay but did not increase the severity of acute (3.75 days) intestinal normal tissue toxicity or late toxicity at 29 weeks. Moreover, we showed that romidepsin treatment impaired both homologous recombination and nonhomologous end joining DNA repair pathways, suggesting that the disruption of DNA repair pathways caused by romidepsin is a key mechanism for its radiosensitizing effect in bladder cancer cells. CONCLUSIONS: This study demonstrates that romidepsin is an effective radiosensitizer in vitro and in vivo and does not increase the acute and late toxicity after ionizing radiation. Romidepsin is already in clinical use for the cutaneous T-cell lymphoma, but a phase 1 clinical trial of romidepsin as a radiosensitizer could be considered in muscle-invasive bladder cancer.


Assuntos
Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias da Bexiga Urinária/patologia , Acetilação/efeitos dos fármacos , Acetilação/efeitos da radiação , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Depsipeptídeos/efeitos adversos , Inibidores de Histona Desacetilases/efeitos adversos , Histonas/metabolismo , Humanos , Órgãos em Risco/efeitos da radiação , Radiossensibilizantes/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 21(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936587

RESUMO

Gold nanoparticles (GNPs) have demonstrated significant dose enhancement with kilovoltage (kV) X-rays; however, recent studies have shown inconsistent findings with megavoltage (MV) X-rays. We propose to evaluate the radiosensitization effect on U87 glioblastoma (GBM) cells in the presence of 42 nm GNPs and irradiated with a clinical 6 MV photon beam. Cytotoxicity and radiosensitization were measured using MTS and clonogenic cellular radiation sensitivity assays, respectively. The sensitization enhancement ratio was calculated for 2 Gy (SER2Gy) with GNP (100 µg/mL). Dark field and MTS assays revealed high co-localization and good biocompatibility of the GNPs with GBM cells. A significant sensitization enhancement of 1.45 (p = 0.001) was observed with GNP 100 µg/mL. Similarly, at 6 Gy, there was significant difference in the survival fraction between the GBM alone group (mean (M) = 0.26, standard deviation (SD) = 0.008) and the GBM plus GNP group (M = 0.07, SD = 0.05, p = 0.03). GNPs enabled radiosensitization in U87 GBM cells at 2 Gy when irradiated using a clinical platform. In addition to the potential clinical utility of GNPs, these studies demonstrate the effectiveness of a robust and easy to standardize an in-vitro model that can be employed for future studies involving metal nanoparticle plus irradiation.


Assuntos
Eletricidade , Glioblastoma/radioterapia , Ouro/farmacologia , Nanopartículas Metálicas/química , Radiossensibilizantes/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Clonais , Humanos , Nanopartículas Metálicas/ultraestrutura
13.
Int J Mol Sci ; 21(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31940975

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70-80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 µM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.


Assuntos
Neoplasias do Tronco Encefálico , Fracionamento da Dose de Radiação , Glioma , Mutação de Sentido Incorreto , Quinuclidinas/farmacologia , Radiossensibilizantes/farmacologia , Proteína Supressora de Tumor p53 , Substituição de Aminoácidos , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Linhagem Celular Tumoral , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Glioma/terapia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
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
15.
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
16.
Int J Radiat Oncol Biol Phys ; 106(4): 867-877, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786278

RESUMO

PURPOSE: The incidence of mesothelioma continues to rise and prognosis remains dismal owing to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of antiapoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of antiapoptotic proteins in the radioresistance of mesothelioma, identifying clinically relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiation therapy in preclinical models. METHODS, MATERIALS AND RESULTS: Mesothelioma cell lines 211H, H2052, and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC50, 0.13-1.42 µmol/L) and radiosensitizing activities (sensitizer enhancement ratios, 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a 3-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells. CONCLUSIONS: Mesothelioma cells exhibit addiction to the antiapoptotic protein Bcl-xL, and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Mesotelioma/patologia , Fragmentos de Peptídeos , Peptidomiméticos/farmacologia , Proteínas Proto-Oncogênicas , Radiossensibilizantes/farmacologia , Proteína bcl-X/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos
17.
Lasers Med Sci ; 35(1): 87-93, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31076924

RESUMO

Melanotic melanoma has high content of melanin and laser can destroy melanin-containing cells through thermal effect. In this study, the therapeutic effect of 808 nm laser therapy was investigated on B16-F10 melanoma tumor growth and tumor-bearing mice survival time. In addition, as laser can destroy melanin as the main cause of melanoma radioresistance, the effect of laser administration to enhance radiation therapy efficacy at B16-F10 cancer cells was evaluated in vitro and in vivo. Laser therapy (1 W/cm2 × 4 min) could cause significant (P < 0.05) inhibition of melanoma tumors' growth (~ 61%) and about three times increase of the tumor-bearing mice survival time in comparison with no-treatment group. In addition, the mice which were treated with 1 W/cm2 × 4 min laser administration plus 6 Gy megavoltage radiation therapy exhibited ~ 68% lesser tumors' volume and 27 days increase of survival time in comparison with 6 Gy irradiated tumor-bearing mice. Also, significantly higher (P < 0.05) tumor necrosis percentage was observed at the histopathological slides of 1 W/cm2 × 4 min laser + RT treated mice tumors (57 ± 12%) in comparison with radiation therapy group (31 ± 10%). Therefore, not only laser therapy can inhibit melanoma tumors' growth per se but also its combination with radiation therapy can cause a significant enhancement of radiation therapy efficacy. The laser administration can be used as a radiosensitizing method for melanotic melanoma radiation therapy.


Assuntos
Eletricidade , Terapia a Laser , Melanoma Experimental/radioterapia , Animais , Linhagem Celular Tumoral , Feminino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Necrose , Radiossensibilizantes/farmacologia , Análise de Sobrevida , Carga Tumoral/efeitos da radiação
18.
Biochim Biophys Acta Gen Subj ; 1864(1): 129457, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678144

RESUMO

BACKGROUND: Adenosine receptors are involved in tumor growth, progression, and response to therapy. Among them, A2B receptor is highly expressed in various tumors. Furthermore, ionizing radiation induces translocation of epidermal growth factor receptor (EGFR), which promotes DNA repair and contributes to radioresistance. We hypothesized that A2B receptor might be involved in the translocation of EGFR. METHODS: We investigated whether A2B receptor is involved in EGFR translocation and DNA damage response (γH2AX/53BP1 focus formation) of lung cancer cells by means of immunofluorescence studies. Radiosensitivity was evaluated by colony formation assay after γ-irradiation. RESULTS: A2B receptor was expressed at higher levels in cancer cells than in normal cells. A2B receptor antagonist treatment or A2B receptor knockdown suppressed EGFR translocation, γH2AX/53BP1 focus formation, and colony formation of lung cancer cell lines A549, calu-6 and NCI-H446, compared with a normal cell line (beas-2b). γ-Irradiation-induced phosphorylation of src and EGFR was also attenuated by suppression of A2B receptor expression. CONCLUSION: Activation of A2B receptor mediates γ-radiation-induced translocation of EGFR and phosphorylation of src and EGFR, thereby promoting recovery of irradiated lung cancer cells from DNA damage. GENERAL SIGNIFICANCE: Our results indicate that A2B receptors contribute to radiation resistance in a cancer-cell-specific manner, and may be a promising target for radiosensitizers in cancer radiotherapy.


Assuntos
Neoplasias Pulmonares/radioterapia , Tolerância a Radiação/genética , Receptor A2B de Adenosina/genética , Células A549 , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Histonas/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosforilação/efeitos da radiação , Radiação , Radiossensibilizantes/farmacologia , Translocação Genética/efeitos dos fármacos , Translocação Genética/efeitos da radiação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Quinases da Família src/genética
19.
PLoS One ; 14(12): e0225931, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800616

RESUMO

High concentrations of antioxidants in cancer cells are huge obstacle in cancer radiotherapy. Erastin was first discovered as an inducer of iron-dependent cell death called ferroptosis accompanied by antioxidant depletion caused by cystine glutamate antiporter inhibition. Therefore, treatment with erastin is expected to potentially enhance cellular radiosensitivity. In this study, we investigated the influence of treatment with erastin on the radiation efficiency against cancers. The clonogenic ability, glutathione peroxidase 4 (GPX4) expression, and glutathione concentration were evaluated using HeLa and NCI-H1975 adenocarcinoma cell lines treated with erastin and/or X-ray irradiation. For in vivo studies, NCI-H1975 cells were transplanted in the left shoulder of nude mice, and then radiosensitizing effect of erastin and glutathione concentration in the cancer were evaluated. Treatment with erastin induced ferroptosis and decreased the concentration of glutathione and GPX4 protein expression levels in the two tumor cell lines. Moreover, erastin enhanced X-ray irradiation-induced cell death in both human tumor cell lines. Furthermore, erastin treatment of a tumor-transplanted mouse model similarly demonstrated the radiosensitizing effect and decrease in intratumoral glutathione concentration in the in vitro study. In conclusion, our study demonstrated the radiosensitizing effect of erastin on two adenocarcinoma cell lines and the tumor xenograft model accompanied by glutathione depletion, indicating that ferroptosis inducers that reduce glutathione concentration could be applied as a novel cancer therapy in combination with radiotherapy.


Assuntos
Antineoplásicos/farmacologia , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Piperazinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801300

RESUMO

Mechanistic approaches to modeling the effects of ionizing radiation on cells are on the rise, promising a better understanding of predictions and higher flexibility concerning conditions to be accounted for. In this work we modified and extended a previously published mechanistic model of cell survival after photon irradiation under hypoxia to account for radiosensitization caused by deficiency or inhibition of DNA damage repair enzymes. The model is shown to be capable of describing the survival data of cells with DNA damage repair deficiency, both under norm- and hypoxia. We find that our parameterization of radiosensitization is invariant under change of oxygen status, indicating that the relevant parameters for both mechanisms can be obtained independently and introduced freely to the model to predict their combined effect.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Reparo do DNA/efeitos da radiação , Proteína Quinase Ativada por DNA/genética , Fótons , Inibidores de Proteínas Quinases/farmacologia , Radiossensibilizantes/farmacologia , Células A549 , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Células CHO , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Cricetulus , DNA/genética , DNA/metabolismo , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Proteína Quinase Ativada por DNA/deficiência , Relação Dose-Resposta à Radiação , Expressão Gênica , Humanos , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , Oxigênio/farmacologia
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