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1.
Tumour Biol ; 43(1): 225-247, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34542050

RESUMO

BACKGROUND: The limitations of surgery, radiotherapy, and chemotherapy in cancer treatment and the increase in the application of nanomaterials in the field of biomedicine have promoted the use of nanomaterials in combination with radiotherapy for cancer treatment. OBJECTIVE: To improve the efficiency of cancer treatment, curcumin-naringenin loaded dextran-coated magnetic nanoparticles (CUR-NAR-D-MNPs) were used as chemotherapy and in combination with radiotherapy to verify their effectiveness in treating tumors. METHODS: CUR-NAR-D-MNPs were prepared and studied by several characterization methods. Median inhibitory concentration (IC50) and cellular toxicity were evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell death and radiosensitization were studied by acridine orange/ethidium bromide dual staining of MCF-7 human breast cancer cells. RESULTS: CUR-NAR-D-MNPs induce apoptosis and inhibited cell proliferation through reactive oxygen species (ROS) generation. CUR-NAR-D-MNPs used alone had a certain therapeutic effect on tumors. CUR-NAR-D-MNPs plus radiotherapy significantly reduced the tumor volume and led to cell cycle arrest and induction of apoptosis through modulation of P53high, P21high, TNF-αlow, CD44low, and ROShigh signalingCONCLUSIONS:CUR-NAR-D-MNPs are effective in the treatment of tumors when combined with radiotherapy, and show radiosensitization effects against cancer proliferation in vitro and in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Curcumina/química , Flavanonas/química , Nanopartículas de Magnetita/química , Radiossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia , Curcumina/farmacologia , Curcumina/uso terapêutico , Dextranos/química , Feminino , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Humanos , Células MCF-7 , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Photochem Photobiol B ; 223: 112303, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34509718

RESUMO

Hypericin (Hy) is a hydrophobic photosensitizer used in photodynamic therapy for cancer therapeutic. In this study, Hy-loaded oil-in-water (O/W) nanoemulsions (NEs) were produced by the ultrasonication method combing different biocompatible oils and surfactants to enhance Hy aqueous solubility and bioavailability. Experimental parameters were optimized by the characterization of droplet size, zeta potential, and physicochemical properties. In vitro studies based on the release profile, cytotoxicity, cell morphology, and Hy intracellular accumulation were assayed. Hy at 100 mg L-1 was incorporated into the low viscosity (~0.005 Pa s) NEs with spherical droplets averaging 20-40 nm in size and polydispersity index <0.02. Hy release from the NE was significantly higher (4-fold) than its suspension (p < 0.001). The NEs demonstrated good physical stability during storage at 5 °C for at least six months. The Hy-loaded NEs exhibited an IC50 value 6-fold lower than Hy suspension during PDT against breast cancer cell lines (MCF-7). Cell microscopy imaging confirmed the increased cytotoxic effects of Hy-loaded NEs, showing damaged and apoptotic cells. Confocal laser scanning microscopy evidenced greater Hy delivery through NE into MCF-7 cells followed by improved intracellular ROS generation. Our results suggest that the Hy-loaded NEs can improve hypericin efficacy and assist Hy-PDT's preclinical development as a cancer treatment.


Assuntos
Antracenos/química , Emulsões/química , Nanoestruturas/química , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Radiossensibilizantes/química , Antracenos/metabolismo , Antracenos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos/efeitos da radiação , Estabilidade de Medicamentos , Humanos , Luz , Células MCF-7 , Óleos/química , Perileno/química , Perileno/metabolismo , Perileno/farmacologia , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sonicação , Temperatura , Água/química
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360994

RESUMO

Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Glicina/análogos & derivados , Radiossensibilizantes/farmacologia , Sulfonas/farmacologia , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Glicina/farmacologia , Humanos
4.
Front Public Health ; 9: 699822, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395371

RESUMO

The number of proton therapy facilities and the clinical usage of high energy proton beams for cancer treatment has substantially increased over the last decade. This is mainly due to the superior dose distribution of proton beams resulting in a reduction of side effects and a lower integral dose compared to conventional X-ray radiotherapy. More recently, the usage of metallic nanoparticles as radiosensitizers to enhance radiotherapy is receiving growing attention. While this strategy was originally intended for X-ray radiotherapy, there is currently a small number of experimental studies indicating promising results for proton therapy. However, most of these studies used low proton energies, which are less applicable to clinical practice; and very small gold nanoparticles (AuNPs). Therefore, this proof of principle study evaluates the radiosensitization effect of larger AuNPs in combination with a 200 MeV proton beam. CHO-K1 cells were exposed to a concentration of 10 µg/ml of 50 nm AuNPs for 4 hours before irradiation with a clinical proton beam at NRF iThemba LABS. AuNP internalization was confirmed by inductively coupled mass spectrometry and transmission electron microscopy, showing a random distribution of AuNPs throughout the cytoplasm of the cells and even some close localization to the nuclear membrane. The combined exposure to AuNPs and protons resulted in an increase in cell killing, which was 27.1% at 2 Gy and 43.8% at 6 Gy, compared to proton irradiation alone, illustrating the radiosensitizing potential of AuNPs. Additionally, cells were irradiated at different positions along the proton depth-dose curve to investigate the LET-dependence of AuNP radiosensitization. An increase in cytogenetic damage was observed at all depths for the combined treatment compared to protons alone, but no incremental increase with LET could be determined. In conclusion, this study confirms the potential of 50 nm AuNPs to increase the therapeutic efficacy of proton therapy.


Assuntos
Nanopartículas Metálicas , Terapia com Prótons , Radiossensibilizantes , Ouro , Humanos , Microscopia Eletrônica de Transmissão , Radiossensibilizantes/farmacologia
5.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445354

RESUMO

PURPOSE: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new "target". Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. CONCLUSIONS: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled "oxygenate, target, use, and digest". In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.


Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Hipóxia Tumoral/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Humanos , Terapia de Alvo Molecular/tendências , Neoplasias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Terapias em Estudo/métodos , Terapias em Estudo/tendências
6.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361743

RESUMO

While investigating the possible synergistic effect of the conventional anticancer therapies, which, taken individually, are often ineffective against critical tumors, such as central nervous system (CNS) ones, the design of a theranostic nanovector able to carry and deliver chemotherapy drugs and magnetic hyperthermic agents to the target radiosensitizers (oxygen) was pursued. Alongside the original formulation of polymeric biodegradable oxygen-loaded nanostructures, their properties were fine-tuned to optimize their ability to conjugate therapeutic doses of drugs (doxorubicin) or antitumoral natural substances (curcumin). Oxygen-loaded nanostructures (diameter = 251 ± 13 nm, ζ potential = -29 ± 5 mV) were finally decorated with superparamagnetic iron oxide nanoparticles (SPIONs, diameter = 18 ± 3 nm, ζ potential = 14 ± 4 mV), producing stable, effective and non-agglomerating magnetic nanovectors (diameter = 279 ± 17 nm, ζ potential = -18 ± 7 mV), which could potentially target the tumoral tissues under magnetic driving and are monitorable either by US or MRI imaging.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Quitosana/química , Hipertermia Induzida/métodos , Nanopartículas de Magnetita/química , Radiossensibilizantes/farmacologia , Nanomedicina Teranóstica/métodos , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Meios de Contraste/síntese química , Meios de Contraste/farmacologia , Curcumina/química , Curcumina/farmacologia , Sulfato de Dextrana/química , Doxorrubicina/química , Doxorrubicina/farmacologia , Composição de Medicamentos/métodos , Humanos , Cinética , Nanopartículas de Magnetita/ultraestrutura , Oxigênio/química , Oxigênio/farmacologia , Radiossensibilizantes/síntese química
7.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445646

RESUMO

Albeit the effort to develop targeted therapies for patients with high-grade gliomas (WHO grades III and IV) is evidenced by hundreds of current clinical trials, radiation remains one of the few effective therapeutic options for them. This review article analyzes the updates on the topic "radiotherapy of high-grade gliomas" during the period 1 January 2021-30 June 2021. The high number of articles retrieved in PubMed using the search terms ("gliom* and radio*") and manually selected for relevance indicates the feverish research currently ongoing on the subject. During the last semester, significant advances were provided in both the preclinical and clinical settings concerning the diagnosis and prognosis of high-grade gliomas, their radioresistance, and the inevitable side effects of their treatment with radiation. The novel information concerning tumor radiosensitization was of special interest in terms of therapeutic perspective and was discussed in detail.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Radiossensibilizantes/farmacologia , Radioterapia/métodos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Glioma/tratamento farmacológico , Glioma/patologia , Humanos
8.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361793

RESUMO

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.


Assuntos
Antineoplásicos/química , Química Click/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Radiossensibilizantes/química , Radioimunoterapia/métodos , Alcinos/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Azidas/química , Reação de Cicloadição/métodos , Ciclo-Octanos/química , Elétrons , Compostos Heterocíclicos com 1 Anel/química , Humanos , Concentração de Íons de Hidrogênio , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Neoplasias/química , Neoplasias/imunologia , Neoplasias/patologia , Fotoquimioterapia/métodos , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/farmacologia
9.
Acta Biomater ; 131: 508-518, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34214663

RESUMO

Radio-sensitization is highly desired to reduce side-effect of the harsh dose of radiation therapy (RT), for which nanoparticles with high atomic number elements provide a promising tool. However, insufficient knowledge on utilizing the interaction between nanoparticles and cancerous cells hampers the improvement of therapeutic outcome. We herein employed NaGdF4:Yb,Er nano-crystals as the sensitizer, and modified them with a tumor targeting agent and a mitochondria targeting moiety, separately and jointly, to achieve varied extent of mitochondrial accumulation. We observed that NaGdF4:Yb,Er nano-crystal, even unmodified with targeting ligands, is effective for radio-sensitization. Furthermore, the extent of mitochondrial targeting was responsible for sensitization efficiency both in vitro and in vitro. By RNA sequencing technique, the result was ascribed to the reactive oxygen species (ROS) mediated TNF-JNK pathway and cell cycle arrest besides breaking DNA, in contrast to only DNA damage only with those untargeted nanoparticles. Our work indicated that ROS generated by the irradiation can be utilized by activating an alternative apoptotic pathway with mitochondrial targeting nanoparticles, and therefore may suggest an approach for the enhancement of radio-sensitization. STATEMENT OF SIGNIFICANCE: Radiosensitization by nanoparticles could reduce the burden of cancer due to lowering the dose of radiation therapy and reducing side-effect. How to fully utilize the interactions of irradiation-nanoparticles-biotissues remains a challenge for improving the outcome of radiosensitization. In this manuscript, by modifying tumor-targeting and mitochondria-targeting ligands on nanoparticles, separately and jointly, we demonstrated that the radiosensitization efficiency of NaGdF4:Yb,Er nanoparticle depends on the extent of accumulation near mitochondria. By RNA-seq technique, the RT sensitization with mitochondrial targeting was ascribed to ROS-mediated TNF-JNK pathway and cell cycle arrest, in contrast to only DNA breaks with untargeted nanoparticles. The results suggested a strategy for better utilization of the energy of therapeutic irradiation and demonstrate that subcellular targeting is a potent factor for designing nanoparticulate radiosensitizers.


Assuntos
Nanopartículas , Neoplasias , Radiossensibilizantes , Humanos , Mitocôndrias , Radiossensibilizantes/farmacologia , Espécies Reativas de Oxigênio
10.
Anticancer Res ; 41(7): 3337-3341, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230129

RESUMO

BACKGROUND/AIM: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive type of primary brain tumor and a cornerstone in its treatment is radiotherapy (RT). However, RT for GBM is largely ineffective at clinically safe doses, thus, the study of radiosensitizers is of great significance. MATERIALS AND METHODS: With accumulating evidence for the anticancer effect of compounds from cranberry, this study was designed to investigate if cranberry extract (CE) sensitizes GBM to RT in the widely used human glioblastoma cell line U87. We utilized clonogenic survival assays, cell proliferation assays, and caspase-3 activity kits. Potential proliferative and apoptotic molecular mechanisms were evaluated by reverse transcription-polymerase chain reaction. RESULTS: We found that CE alone had little effect on the survival of U87 cells. However, RT supplemented by CE significantly inhibited proliferation and promoted apoptosis of U87 cells when compared with RT alone. The proliferation-inhibitory effect of RT/CE might be attributable to the up-regulation of p21, along with the down-regulation of cyclin B and cyclin-dependent kinase 4. This pro-apoptotic effect might additionally be attributable to the down-regulation of survivin. CONCLUSION: These results warrant further study of the potential radiosensitizing capacity of CE in glioblastoma and other cancer types.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Extratos Vegetais/farmacologia , Radiossensibilizantes/farmacologia , Vaccinium macrocarpon/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Regulação para Cima/efeitos dos fármacos
11.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34201963

RESUMO

Pancreatic ductal adenocarcinoma is a devastating disease with a 5-year overall survival of 9% for all stages. Gemcitabine-based chemoradiotherapy for locally advanced pancreatic cancer is highly toxic. We conducted an in vitro study to determine whether poly(ADP-ribose) polymerase-1 inhibition radiosensitized gemcitabine-based chemotherapy. Human pancreatic cancer cell lines, MIA PaCa-2, AsPC-1, BxPC-3 and PANC-1 were treated with gemcitabine (10 nM) and/or olaparib (1 µM). Low-LET gamma single dose of 2, 5 and 10 Gy radiations were carried out. Clonogenic assay, PAR immunoblotting, cell cycle distribution, γH2Ax, necrotic and autophagic cell death quantifications were performed. Treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines, particularly at high dose per fraction A non-cytotoxic concentration of gemcitabine radiosensitized cells, but less than olaparib. Interestingly, olaparib significantly enhanced gemcitabine-based radiosensitization in PDAC cell lines with synergistic effect in BxPC-3 cell line. All cell lines were radiosensitized by the combination of gemcitabine and olaparib, through an increase of unrepaired double-strand, a G2 phase block and cell death. Radiosensitization was increased with high dose of radiation. The combination of olaparib with gemcitabine-based chemoradiotherapy could lead to an enhancement of local control in vivo and an improvement in disease-free survival.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Histonas/metabolismo , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Radiossensibilizantes/farmacologia
12.
Cell Death Dis ; 12(7): 694, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257274

RESUMO

Hypoxia, a characteristic of most human solid tumors, is a major obstacle to successful radiotherapy. While moderate acute hypoxia increases cell survival, chronic cycling hypoxia triggers adaptation processes, leading to the clonal selection of hypoxia-tolerant, apoptosis-resistant cancer cells. Our results demonstrate that exposure to acute and adaptation to chronic cycling hypoxia alters the balance of Bcl-2 family proteins in favor of anti-apoptotic family members, thereby elevating the apoptotic threshold and attenuating the success of radiotherapy. Of note, inhibition of Bcl-2 and Bcl-xL by BH3-mimetic ABT-263 enhanced the sensitivity of HCT116 colon cancer and NCI-H460 lung cancer cells to the cytotoxic action of ionizing radiation. Importantly, we observed this effect not only in normoxia, but also in severe hypoxia to a similar or even higher extent. ABT-263 furthermore enhanced the response of xenograft tumors of control and hypoxia-selected NCI-H460 cells to radiotherapy, thereby confirming the beneficial effect of combined treatment in vivo. Targeting the Bcl-2 rheostat with ABT-263, therefore, is a particularly promising approach to overcome radioresistance of cancer cells exposed to acute or chronic hypoxia with intermittent reoxygenation. Moreover, we found intrinsic as well as ABT-263- and irradiation-induced regulation of Bcl-2 family members to determine therapy sensitivity. In this context, we identified Mcl-1 as a resistance factor that interfered with apoptosis induction by ABT-263, ionizing radiation, and combinatorial treatment. Collectively, our findings provide novel insights into the molecular determinants of hypoxia-mediated resistance to apoptosis and radiotherapy and a rationale for future therapies of hypoxic and hypoxia-selected tumor cell fractions.


Assuntos
Compostos de Anilina/farmacologia , Apoptose , Neoplasias do Colo/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Tolerância a Radiação , Radiossensibilizantes/farmacologia , Sulfonamidas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células HCT116 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrolídeos/metabolismo , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Hipóxia Tumoral , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína bcl-X/metabolismo
13.
Integr Cancer Ther ; 20: 15347354211021920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34105411

RESUMO

This study aimed to evaluate the anticancer and radio-sensitizing efficacy of Zinc Oxide-Caffeic Acid Nanoparticles (ZnO-CA NPs). ZnO-CA NPs were formulated by the conjugation of Zinc Oxide nanoparticles (ZnO NPs) with caffeic acid (CA) that were characterized by Fourier Transform Infrared Spectra (FT-IR), X-ray Diffractometer (XRD), and Transmission Electron Microscopy (TEM). In vitro anticancer potential of ZnO-CA NPs was evaluated by assessing cell viability in the human breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines. In vivo anticancer and radio-sensitizing effects of ZnO-CA NPs in solid Ehrlich carcinoma-bearing mice (EC mice) were also assessed. Treatment of EC mice with ZnO-CA NPs resulted in a considerable decline in tumor size and weight, down-regulation of B-cell lymphoma 2 (BCL2) and nuclear factor kappa B (NF-κB) gene expressions, decreased vascular cell adhesion molecule 1 (VCAM-1) level, downregulation of phosphorylated-extracellular-regulated kinase 1 and 2 (p-ERK1/2) protein expression, DNA fragmentation and a recognizable peak at sub-G0/G1 indicating dead cells' population in cancer tissues. Combined treatment of ZnO-CA NPs with γ-irradiation improved these effects. In conclusion: ZnO-CA NPs exhibit in-vitro as well as in-vivo antitumor activity, which is augmented by exposure of mice to γ-irradiation. Further explorations are warranted previous to clinical application of ZnO-CA NPs.


Assuntos
Carcinoma , Nanopartículas , Radiossensibilizantes , Óxido de Zinco , Animais , Ácidos Cafeicos , Feminino , Camundongos , Radiossensibilizantes/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Óxido de Zinco/farmacologia
14.
Mol Carcinog ; 60(9): 627-643, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34192388

RESUMO

Nonhomologous end joining (NHEJ), one of the major DNA double-strand break repair pathways, plays a significant role in cancer cell proliferation and resistance to radio and chemotherapeutic agents. Previously, we had described a small molecule inhibitor, SCR7, which inhibited NHEJ in a DNA Ligase IV dependent manner. Here, we report that SCR7 potentiates the effect of γ-radiation (IR) that induces DNA breaks as intermediates to eradicate cancer cells. Dose fractionation studies revealed that coadministration of SCR7 and IR (0.5 Gy) in mice Dalton's lymphoma (DLA) model led to a significant reduction in mice tumor cell proliferation, which was equivalent to that observed for 2 Gy dose when both solid and liquid tumor models were used. Besides, co-treatment with SCR7 and 1 Gy of IR further improved the efficacy. Notably, there was no significant change in blood parameters, kidney and liver functions upon combinatorial treatment of SCR7 and IR. Further, the co-treatment of SCR7 and IR resulted in a significant increase in unrepaired DSBs within cancer cells compared to either of the agent alone. Anatomy, histology, and other studies in tumor models confirmed the cumulative effects of both agents in activating apoptotic pathways to induce cytotoxicity by modulating DNA damage response and repair pathways. Thus, we report that SCR7 has the potential to reduce the side effects of radiotherapy by lowering its effective dose ex vivo and in mice tumor models, with implications in cancer therapy.


Assuntos
Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos da radiação , Pirimidinas/farmacologia , Radiação Ionizante , Radiossensibilizantes/farmacologia , Bases de Schiff/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , DNA Ligase Dependente de ATP/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071406

RESUMO

Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-ß binding sites of A549 cells. Treatment with 1-25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.


Assuntos
Alcaloides de Berberina/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células A549 , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Humanos , Microscopia Confocal , Radiação Ionizante , Radiossensibilizantes/farmacologia
16.
Int J Radiat Biol ; 97(9): 1289-1298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34047663

RESUMO

INTRODUCTION: Nowadays, some nanoparticles (NPs) are known and used as radiosensitizers in radiotherapy and radiobiology, due to their desired biological, physical, and chemical effects on cells. This study aimed to evaluate and compare the dose enhancement factor (DEF) and the biological effectiveness of some common NPs through EGSnrc and MCDS Monte Carlo (MC) simulation codes. MATERIALS AND METHODS: To evaluate considered NPs' DEF, a single NP with 50 nm diameter was simulated at the center of concentric spheres. NP irradiations were done with 30, 60, and 100 keV photon energies. The secondary electron spectra were scored at the surface of considered NPs, and the dose values were scored at surrounding water-filled spherical shells which were distributed up to 4000 nm from the NP surface. The electron spectra were used in the MCDS code to obtain different initial DNA damages for the calculation of enhanced relative biological effectiveness (eRBE). RESULTS: By decreasing the photon energy, an increment of DEF was seen for all studied NPs. The maximum DEF at 30, 60, and 100 keV photon energies were respectively related to silver (Ag), gadolinium (Gd), and bismuth (Bi) NPs. The maximum double-strand break (DSB) related (eRBEDSB) values for the 30 keV photon belonged to Ag, while BiNPs showed the maximum values at other photon energies. The minimum eRBEDSB values were also related to iron (Fe) NPs at the entire range of studied photon energies. CONCLUSIONS: The compared nanoscale physical and biological results of our study can be helpful in the selection of optimum NP as a radiosensitizer in future radiobiological studies. Bi, gold (Au), Ag, and platinum (Pt) NPs had great potential, respectively, as radiosensitizers relative to the other studied NPs.


Assuntos
Método de Monte Carlo , Nanopartículas , Radiossensibilizantes/farmacologia , Eficiência Biológica Relativa , Relação Dose-Resposta à Radiação
17.
Radiol Oncol ; 55(3): 305-316, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939900

RESUMO

BACKGROUND: Statins, small molecular 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are widely used to lower cholesterol levels in lipid-metabolism disorders. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer by increasing recurrence free survival. Unfortunately, the underlying mechanisms remain elusive. MATERIALS AND METHODS: Simvastatin, one of the most widely prescribed lipophilic statins was utilized to investigate potential radiosensitizing effects and an impact on cell survival and migration in radioresistant breast cancer cell lines. RESULTS: Compared to parental cell counterparts, radioresistant MDA-MB-231-RR, T47D-RR andAu565-RR cells were characterized by upregulation of 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR) expression accompanied by epithelial-to-mesenchymal transition (EMT) activation. Radioresistant breast cancer cells can be killed by simvastatin via mobilizing of a variety of pathways involved in apoptosis and autophagy. In the presence of simvastatin migratory abilities and vimentin expression is diminished while E-cadherin expression is increased. CONCLUSIONS: The present study suggests that simvastatin may effectively eradicate radioresistant breast carcinoma cells and diminish their mesenchymal phenotypes.


Assuntos
Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sinvastatina/farmacologia , Morte Celular Autofágica/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Transição Epitelial-Mesenquimal , Feminino , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Regulação para Cima
18.
Int J Radiat Biol ; 97(7): 943-957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979259

RESUMO

PURPOSE: Herein we describe the in vitro and in vivo activity of FK228 (Romidepsin), an inhibitor of class I HDACs, in counteracting and radiosensitizing embryonal (ERMS, fusion-negative) and alveolar (ARMS, fusion-positive) rhabdomyosarcoma (RMS). METHODS: RH30 (ARMS, fusion-positive) and RD (ERMS, fusion-negative) cell lines and human multipotent mesenchymal stromal cells (HMSC) were used. Flow cytometry analysis, RT-qPCR, western blotting and enzymatic assays were performed. Irradiation was delivered by using an x-6 MV photon linear accelerator. FK228 (1.2 mg/kg) in vivo activity, combined or not with radiation therapy (2 Gy), was assessed in murine xenografts. RESULTS: Compared to HMSC, RMS expressed low levels of class I HDACs. In vitro, FK228, as single agents, reversibly downregulated class I HDACs expression and activity and induced oxidative stress, DNA damage and a concomitant growth arrest associated with PARP-1-mediated transient non-apoptotic cell death. Surviving cells upregulated the expression of cyclin A, B, D1, p27, Myc and activated PI3K/Akt/mTOR and MAPK signaling, known to be differently involved in cancer chemoresistance. Interestingly, while no radiosensitizing effects were detected, in vitro or in vivo, on RD cells, FK228 markedly radiosensitized RH30 cells by impairing antioxidant and DSBs repair pathways in vitro. Further, FK228 when combined with RT in vivo significantly reduced tumor mass in mouse RH30 xenografts. CONCLUSION: FK228 did not show antitumor activity as a single agent whilst its combination with RT resulted in radiosensitization of fusion-positive RMS cells, thus representing a possible strategy for the treatment of the most aggressive RMS subtype.


Assuntos
Transformação Celular Neoplásica , Depsipeptídeos/farmacologia , Fenótipo , Radiossensibilizantes/farmacologia , Rabdomiossarcoma/patologia , Animais , Apoptose/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Linhagem Celular Tumoral , Humanos , Camundongos
19.
Int J Radiat Oncol Biol Phys ; 111(2): 515-527, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34044093

RESUMO

PURPOSE: Artemis and DNA Ligase IV are 2 critical elements in the nonhomologous end joining pathway of DNA repair, acting as the nuclease and DNA ligase, respectively. Enhanced cellular radiosensitivity by inhibition of either protein contributes to a promising approach to develop molecular targeted radiosensitizers. The interaction between Artemis and DNA Ligase IV is required for the activation of Artemis as nuclease at 3'overhang DNA; thus, we aim to generate an inhibitory peptide targeting the interaction between Artemis and DNA Ligase IV for novel radiosensitizer development. METHODS AND MATERIALS: We synthesized the peptide BAL, which consists of the interaction residues of Artemis to DNA Ligase IV. The radiosensitization effect of BAL was evaluated by colony formation assay. The effects of BAL on radiation-induced DNA repair were evaluated with Western blotting and immunofluorescence. The effects of BAL on cell proliferation, cell cycle arrest, and cell apoptosis were assessed via CCK-8 and flow cytometry assays. The potential synergistic effects of BAL and irradiation in vivo were investigated in a xenograft mouse model. RESULTS: The generated peptide BAL blocking the interaction between Artemis and DNA Ligase IV significantly enhanced the radiosensitivity of GBC-SD and HeLa cell lines. BAL prolonged DNA repair after irradiation; BAL and irradiation showed synergistic effects on cell proliferation, cell cycle, and cell apoptosis, and these functions are all DNA Ligase IV-related. Finally, we confirmed the endogenous radiosensitization effect of BAL in a xenograft mouse model. CONCLUSIONS: The inhibitory peptide BAL targeting the binding of Artemis and DNA Ligase IV successfully functions as a novel radiosensitizer that delays DNA repair and synergizes with irradiation to inhibit cell proliferation, induce cell cycle arrest, and promote cell apoptosis.


Assuntos
DNA Ligase Dependente de ATP/metabolismo , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Neoplasias/radioterapia , Peptídeos/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos da radiação , DNA Ligase Dependente de ATP/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Endonucleases/antagonistas & inibidores , Células HeLa , Humanos , Masculino , Camundongos , Neoplasias/patologia
20.
J Mater Chem B ; 9(22): 4510-4522, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34027529

RESUMO

The development of highly integrated multifunctional nanomaterials with a superadditive therapeutic effect and good safety is an urgent but challenging task in cancer therapy research. The present study aims to design a nanoplatform that offers the opportunity to enhance antitumor activity while minimizing side effects. Given the Au-mediated X-ray radiation enhancement and the ability of Fe-based nanomaterials to create reactive oxygen species (ROS) and DNA damage, we anticipated that bimetallic Fe3O4-Au heterodimer would bring strong radiosensitizing capacity. Fe3O4-Au heterodimer surface was covered with bovine serum albumin (BSA) to achieve good surface functionality, stability and prolonged blood circulation. Folic acid (FA) moieties were added to the nanoformulation to increase tumor-homing, specificity and uptake. Finally, curcumin (CUR) was incorporated into the nanoparticle to function as a natural anticancer agent. The integration of all these components has yielded a single nanoplatform, Fe3O4-Au-BSA-FA-CUR, capable of successfully fulfilling the mission of superadditive cancer therapy to avoid the risks of organ removal surgery. The efficacy of the proposed nanoplatform was investigated in vitro and in vivo. High radiosensitizing ability, X-ray-induced ROS generation and DNA damage, and good biocompatibility were demonstrated through in vitro experiments. Also, the administration of Fe3O4-Au-BSA-FA-CUR with X-ray irradiation completely eradicated the tumor without any mortality and toxicity in healthy tissues in vivo. Our results highlight the potential of CUR-loaded Fe3O4-Au-BSA-FA heteronanostructure to enable synergistic localized radiochemotherapy and open up a new door to attractive possibilities that warrant further exploration.


Assuntos
Neoplasias da Mama/terapia , Compostos Férricos/farmacologia , Ouro/farmacologia , Radiossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Quimiorradioterapia , Camundongos
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