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1.
Int J Mol Sci ; 25(17)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39273472

RESUMO

Conventional X-ray therapy (XRT) is commonly applied to suppress cancerous tumors; however, it often inflicts collateral damage to nearby healthy tissue. In order to provide a better conformity of the dose distribution in the irradiated tumor, proton therapy (PT) is increasingly being used to treat solid tumors. Furthermore, radiosensitization with gold nanoparticles (GNPs) has been extensively studied to increase the therapeutic ratio. The mechanism of radiosensitization is assumed to be connected to an enhancement of the absorbed dose due to huge photoelectric cross-sections with gold. Nevertheless, numerous theoretical studies, mostly based on Monte Carlo (MC) simulations, did not provide a consistent and thorough picture of dose enhancement and, therefore, the radiosensitization effect. Radiosensitization by nanoparticles in PT is even less studied than in XRT. Therefore, we investigate the physics picture of GNP-enhanced RT using an MC simulation with Geant4 equipped with the most recent physics models, taking into account a wide range of physics processes relevant for realistic PT and XRT. Namely, we measured dose enhancement factors in the vicinity of GNP, with diameters ranging from 10 nm to 80 nm. The dose enhancement in the vicinity of GNP reaches high values for XRT, while it is very modest for PT. The macroscopic dose enhancement factors for realistic therapeutic GNP concentrations are rather low for all RT scenarios; therefore, other physico-chemical and biological mechanisms should be additionally invoked for an explanation of the radiosensitization effect observed in many experiments.


Assuntos
Ouro , Nanopartículas Metálicas , Método de Monte Carlo , Ouro/química , Nanopartículas Metálicas/química , Humanos , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Dosagem Radioterapêutica , Terapia com Prótons/métodos , Radiossensibilizantes/química , Simulação por Computador , Radioterapia/métodos , Radiometria/métodos
2.
Radiat Oncol ; 19(1): 119, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267113

RESUMO

Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Radiossensibilizantes , Glioblastoma/radioterapia , Glioblastoma/imunologia , Animais , Camundongos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/imunologia , Humanos , Radiossensibilizantes/administração & dosagem , Nanopartículas/química , Barreira Hematoencefálica/efeitos da radiação , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Medicamentos , Linhagem Celular Tumoral
3.
Cell Physiol Biochem ; 58(5): 459-476, 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39248186

RESUMO

BACKGROUND/AIMS: One of the treatments for breast cancer is surgical resection of the tumour and prevention of recurrence with postoperative radiotherapy. Unfortunately, radiotherapy is not always effective enough due to the low sensitivity of cancer cells to ionising radiation. This study aimed to evaluate the radiosensitising properties of resveratrol, piceatannol and polydatin on breast cancer cells, which differ in the presence of hormonal receptors on their surface. METHODS: The experimental part was carried out on triple-negative breast cancer cells (HCC38) and hormone-dependent cells (MCF7). The study assessed the level of cell death, changes in the expression of genes (BAX, BCL-2) and proteins related to the apoptosis process (CASPASE 3, 8 and P53), changes in the expression of antioxidant enzymes (CATALASE, SOD, GPx1/2) and NRF-2. Additionally, the expression level of RAD51 protein and histone H2AX, which are involved in DNA repair processes, was assessed. Statistical significance was evaluated by a two-way analysis of variance (ANOVA) followed by Tukey's post hoc test (p < 0.05). RESULTS: Ionising radiation in combination with resveratrol or piceatannol activates the apoptosis process by internal and external pathways. Greater sensitivity of MCF7 cells compared to HCC38 cells to ionising radiation in combination with resveratrol is associated with a weaker antioxidant response of cells and reduced intensity of DNA damage repair. DNA repair induced by ionising radiation occurs more effectively in HCC38 cells than in MCF7 cells. CONCLUSION: Resveratrol has the highest radiosensitising potential among the tested stilbene for cells of both lines. The effectiveness of ionizing radiation in combination with resveratrol (to a lesser extent with piceatannol) is more significant in MCF7 than in HCC38 cells.


Assuntos
Apoptose , Radiação Ionizante , Radiossensibilizantes , Resveratrol , Estilbenos , Humanos , Estilbenos/farmacologia , Resveratrol/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Feminino , Radiossensibilizantes/farmacologia , Linhagem Celular Tumoral , Células MCF-7 , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Neoplasias da Mama/tratamento farmacológico , Histonas/metabolismo , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Rad51 Recombinase/metabolismo , Caspase 3/metabolismo , Glucosídeos
4.
Colloids Surf B Biointerfaces ; 244: 114137, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39116601

RESUMO

BACKGROUND: Overcoming radio-resistance and enhance radio-sensitivity to obtain desired therapeutic outcome plays an important role in treating cancer. METHODS: Here we constructed a versatile enzyme-like nano-radiosensitizer MDP. MDP is composed of MnCO decorated and Ru-based nanozyme with triphenylphosphine (TPP) group coordinated on the surface. RESULTS: Due to the mitochondria-targeting ability of TPP and enhanced permeability and retention effect (EPR) effect of MDP, MDP accumulated in the mitochondria of tumor cells. Therefore, quantities of reactive oxygen species were produced via multiple enzyme-like properties including peroxidase (POD) and catalase (CAT) in a tumor microenvironment mimicking status. In additional, more energy of radiation ionizing was deposed in tumor site via Compton effect and secondary electron scattering by Ru element. Impressively, it was disclosed that the nanozyme can act as a cGAS-STING agonist to provoke immune response of the system, which hereby further elevated this combined therapy. CONCLUSIONS: Collectively, we fabricated a novel nanozyme with POD and CAT mimicking properties for the combination therapy of catalytical therapy, radiotherapy as well as immune therapy to eliminate cancer.


Assuntos
Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Animais , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Catálise , Nanopartículas/química , Rutênio/química , Rutênio/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Propriedades de Superfície , Tamanho da Partícula , Peroxidase/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-39109509

RESUMO

Radiotherapy is an invaluable tool in the treatment of cancer. However, when used as a monotherapy, it fails to provide curative outcomes. Chemotherapy drugs are often included to boost the effects of radiation. Key classes of radiosensitizing drugs include platinum compounds, anthracyclines, antimetabolites, taxanes, topoisomerase inhibitors, alkylating agents, and DNA damage repair inhibitors. Chemoradiotherapy suffers from not only systemic toxicities from chemotherapy drugs but also synergistic radiation toxicity as well. It is critical to deliver radiosensitizing molecules to tumor cells while avoiding adjacent healthy tissues. Currently, nanomedicine provides an avenue for tumor specific delivery of radiosensitizers. Nanoscale delivery vehicles can be synthesized from lipids, polymers, or inorganic materials. Additionally, nanomedicine encompasses stimuli responsive particles including prodrug formulation for tumor specific activation. Clinically, nanomedicine and radiotherapy are intertwined with approved formulation including DOXIL and Abraxane. Though many challenges remain, the ongoing progress evidences a promising future for both nanomedicine and chemoradiotherapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.


Assuntos
Quimiorradioterapia , Sistemas de Liberação de Medicamentos , Nanomedicina , Neoplasias , Humanos , Animais , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Radiossensibilizantes/uso terapêutico , Radiossensibilizantes/química
6.
IET Nanobiotechnol ; 2024: 3786627, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144410

RESUMO

Background: Naringenin has shown great promise in the realm of cancer therapeutics, demonstrating excellent cytotoxic action toward cancer cells and the enhanced effects of radiation therapy in vitro. However, the medicinal value of naringenin is severely limited clinically by poor bioavailability. Thus, multiple drug-delivery strategies for overcoming this limitation have been developed, of which liposomes are considered the most suitable due to their amphiphilic, modifiable, and biocompatible characteristics. In this study, we investigated the role of naringenin and liposomal-delivered naringenin as adjuncts to radiotherapy in the MDA-MB-231 triple-negative breast cancer cell line in vitro. Materials and Methods: Liposomal-naringenin was synthesized by thin-film hydration and extrusion and was characterized by spectrophotometry, dynamic light scattering, and zeta potential. The effects of free-from naringenin and liposomal-naringenin were evaluated toward MDA-MB-231 cell viability when combined with varying doses of radiation. Additionally, cell growth patterns, morphology, and colony formation were evaluated. Results: The analysis demonstrated IC50 values of 387.5 and 546.6 µg/ml for naringenin and liposomal-naringenin, respectively. Naringenin and liposomal-naringenin significantly lowered cell viability, proliferation, and colony formation dose-dependently, as compared to radiation in isolation. Conclusion: The findings presented herein concur with previous accounts of the radiosensitizing potential of naringenin and further highlight the considerable biomedical application of liposomal-naringenin within the realm of radiotherapy.


Assuntos
Sobrevivência Celular , Flavanonas , Lipossomos , Radiossensibilizantes , Neoplasias de Mama Triplo Negativas , Flavanonas/química , Flavanonas/farmacologia , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Lipossomos/química , Linhagem Celular Tumoral , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Sobrevivência Celular/efeitos dos fármacos , Feminino , Proliferação de Células/efeitos dos fármacos , Células MDA-MB-231
7.
Chem Biol Drug Des ; 104(2): e14611, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39152534

RESUMO

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti-CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26-R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26-R cells were pretreated with or without BE, followed by transfection with pcDNA-NC and pcDNA-JAK2. The proliferation of CT26-R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26-R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p-STAT3, JAK2, PD-L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p-STAT3, JAK2, and PD-L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA-JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway.


Assuntos
Apoptose , Neoplasias Colorretais , Flavanonas , Janus Quinase 2 , Camundongos Endogâmicos BALB C , Tolerância a Radiação , Fator de Transcrição STAT3 , Transdução de Sinais , Janus Quinase 2/metabolismo , Flavanonas/farmacologia , Flavanonas/química , Flavanonas/uso terapêutico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Animais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Radiossensibilizantes/química
8.
Phytother Res ; 38(8): 4151-4167, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39136618

RESUMO

Despite active clinical trials on the use of Oleandrin alone or in combination with other drugs for the treatment of solid tumors, the potential synergistic effect of Oleandrin with radiotherapy remains unknown. This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase-mediated radiosensitization in lung cancer. Various assays, including clonogenic, Comet, immunofluorescence staining, apoptosis and Cell cycle assays, were conducted to evaluate the impact of oleandrin on radiation-induced double-strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double-strand break repair. The efficacy and toxicity of the combined therapy were assessed in a preclinical xenotransplantation model. Functionally, Oleandrin weakens the DNA damage repair ability and enhances the radiation sensitivity of lung cells. Mechanistically, Oleandrin inhibits ATM and ATR kinase activities, blocking the transmission of ATM-CHK2 and ATR-CHK1 cell cycle checkpoint signaling axes. This accelerates the passage of tumor cells through the G2 phase after radiotherapy, substantially facilitating the rapid entry of large numbers of inadequately repaired cells into mitosis and ultimately triggering mitotic catastrophe. The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Cardenolídeos , Dano ao DNA , Neoplasias Pulmonares , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Animais , Cardenolídeos/farmacologia , Dano ao DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Reparo do DNA/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células A549
9.
Molecules ; 29(16)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39203014

RESUMO

Boron-enhanced proton therapy has recently appeared as a promising approach to increase the efficiency of proton therapy on tumor cells, and this modality can further be improved by the use of boron nanoparticles (B NPs) as local sensitizers to achieve enhanced and targeted therapeutic outcomes. However, the mechanisms of tumor cell elimination under boron-enhanced proton therapy still require clarification. Here, we explore possible molecular mechanisms responsible for the enhancement of therapeutic outcomes under boron NP-enhanced proton therapy. Spherical B NPs with a mode size of 25 nm were prepared by methods of pulsed laser ablation in water, followed by their coating by polyethylene glycol to improve their colloidal stability in buffers. Then, we assessed the efficiency of B NPs as sensitizers of cancer cell killing under irradiation with a 160.5 MeV proton beam. Our experiments showed that the combined effect of B NPs and proton irradiation induces an increased level of superoxide anion radical generation, which leads to the depolarization of mitochondria, a drop in their membrane mitochondrial potential, and the development of apoptosis. A comprehensive gene expression analysis (via RT-PCR) confirmed increased overexpression of 52 genes (out of 87 studied) involved in the cell redox status and oxidative stress, compared to 12 genes in the cells irradiated without B NPs. Other possible mechanisms responsible for the B NPs-induced radiosensitizing effect, including one related to the generation of alpha particles, are discussed. The obtained results give a better insight into the processes involved in the boron-induced enhancement of proton therapy and enable one to optimize parameters of proton therapy in order to maximize therapeutic outcomes.


Assuntos
Apoptose , Boro , Nanopartículas , Terapia com Prótons , Humanos , Boro/química , Boro/farmacologia , Nanopartículas/química , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Neoplasias/radioterapia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos
10.
J Cancer Res Ther ; 20(4): 1284-1292, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39206990

RESUMO

BACKGROUND AND PURPOSE: Radiation therapy is a crucial treatment for nonsmall cell lung cancer (NSCLC), but its effectiveness is limited by the resistance of tumor cells to radiation. This study aimed to evaluate the effect of epicatechin (EC) on radiosensitivity in NSCLC and to determine its relationships with matrix metalloproteinase (MMP)-9. METHODS: MMP-9 expression was detected by Western blotting, and the expression of the DNA damage marker protein was detected by immunofluorescence. Cell viability was assessed using the CCK-8 assay, and cell proliferation was evaluated using the clonogenesis assay. Flow cytometry was used to determine the cell apoptosis, whereas cell migration and invasion were detected using the transwell assays. The cells were treated with ionizing radiation (IR) and EC to verify the sensitizing effect of EC on radiation therapy. RESULTS: MMP-9 expression was elevated in the NSCLC cells and tissues. DNA damage and cell apoptosis were increased, whereas cell vigor, proliferation, migration, and invasion were significantly decreased after IR. MMP-9 knockdown strengthened the impact of IR on the biological behaviors of the cells. EC + IR had the best effect on promoting DNA damage and the biological behaviors of the NSCLC cells; alternatively, the overexpression of MMP-9 weakened the role of EC. CONCLUSIONS: This study shows that EC can downregulate MMP-9 expression, promote DNA damage, reduce cell viability, proliferation, migration, and invasion, and facilitate cell apoptosis, thus, showing potential as a radiosensitizer for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Movimento Celular , Proliferação de Células , Neoplasias Pulmonares , Metaloproteinase 9 da Matriz , Tolerância a Radiação , Humanos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Catequina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia
11.
Clin Nucl Med ; 49(10): 966-967, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39093035

RESUMO

ABSTRACT: A patient with widespread intensely prostate-specific membrane antigen-expressing, BRCA gene mutation-positive bone metastases at the time of prostate cancer diagnosis had progressed on multiple lines of standard therapy. He received 177 Lu-prostate-specific membrane antigen 8.5 GBq augmented by a short course of olaparib radiosensitization and achieved 90% decrease in serum PSA level after a single treatment. His tumor response was much better than expected by predictive dosimetry. However, his marrow radiotoxicity was worse than anticipated and required hospitalization. This suggests radiosensitizing agents to be a double-edged sword that must be carefully considered and balanced during activity prescription.


Assuntos
Lutécio , Ftalazinas , Piperazinas , Neoplasias de Próstata Resistentes à Castração , Radiossensibilizantes , Humanos , Masculino , Ftalazinas/farmacologia , Piperazinas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Radiossensibilizantes/farmacologia , Lutécio/farmacologia , Radioisótopos/farmacologia , Metástase Neoplásica , Antígenos de Superfície , Glutamato Carboxipeptidase II/metabolismo
13.
Anticancer Res ; 44(8): 3295-3306, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39060064

RESUMO

BACKGROUND/AIM: Despite the established antitumor effectiveness and synergistic interactions of melatonin with photon irradiation, its role in carbon-ion radiotherapy remains uncertain. This study aimed to elucidate the mechanisms and potential clinical advantages of combining exogenous melatonin therapy with carbon-ion radiotherapy. MATERIALS AND METHODS: The investigation assessed the impact of combining exogenous melatonin with photon or carbon-ion irradiation on cell-cycle modulation and DNA-repair capability using the melanoma cell line B16F10. RNA sequencing and bioinformatics analysis were conducted to explore mechanisms and evaluate potential clinical benefits, with validation performed on the osteosarcoma cell line LM8. RESULTS: Pre-treatment with melatonin reduced the survival fraction of B16F10 and LM8 cells upon exposure to photon and carbon-ion radiation. Mechanistically, melatonin was found to inhibit G2/M arrest, preserve DNA damage, and suppress key genes involved in DNA double-strand break repair after 8 Gy carbon-ion radiation. Furthermore, RNA sequencing and bioinformatics analysis revealed favorable changes in genes associated with survival and metastasis, highlighting potential clinical significance. LM8 cells treated with melatonin exhibited increased radiosensitivity and suppression of DNA-repair proteins. CONCLUSION: The combination of exogenous melatonin not only heightened radiosensitivity and modulated hallmark tumor gene sets in vitro but also markedly suppressed the efficiency of DNA double-strand break-repair pathway, thus enhancing the cytotoxicity of carbon-ion radiotherapy.


Assuntos
Reparo do DNA , Radioterapia com Íons Pesados , Melatonina , Tolerância a Radiação , Radiossensibilizantes , Melatonina/farmacologia , Linhagem Celular Tumoral , Tolerância a Radiação/efeitos dos fármacos , Camundongos , Animais , Humanos , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Radiossensibilizantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Melanoma Experimental/radioterapia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação
14.
J Cancer Res Ther ; 20(3): 827-831, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-39023590

RESUMO

BACKGROUND: Concurrent chemoradiotherapy now represents the standard of care in locally advanced unresectable squamous cell carcinoma of the head and neck, and the administration of cisplatin in triweekly or weekly schedules is the most commonly used chemotherapeutic agent. However, the chemotherapeutic agent and its scheduling with radiation is still an area of investigation with safer toxicity profile and better response rates. Gemcitabine is a potent radiosensitizer, and non-cytotoxic concentration results in decreased systemic toxicity while maintaining radiosensitization properties. Furthermore, data are emerging for low-dose and long-duration infusion where this strategy is found to be effective and a safe alternative to standard brief infusion. Based on these two strategies, that is, non-cytotoxic concentration with long duration, we have explored the unique possibility of further lowering the toxicity profile without compromising the efficacy. METHOD: Eligible patients of locally advanced unresectable squamous cell carcinoma of the head and neck underwent radiation treatment with concurrent gemcitabine. A total dose of 70 Gy in 35 fractions over a period of seven weeks with conventional fractionation schedule was delivered with cord off after 44 Gy. Concurrent gemcitabine was administered intravenously for over two hours once a week, 1-2 h before radiation and for seven consecutive weeks at 50 mg/m2. RESULT: Fifty-two patients was enrolled in this study, out of which 41 completed the treatment. Fifty-nine percent completed treatment within seven weeks. Sixty-four percent were found to have received more than five cycles. Mean follow-up of patients was found to be 4.9 months. Sixty-eight percent had complete response. Stage III patients achieved more complete response compared to stage IV. There was no site-wise difference in achieving complete response. Patients who have received less than five chemo cycles or completed the treatment in more than seven weeks had less complete response. Sixty-one percent had severe mucositis while 39% developed mild/moderate mucositis. Considering skin toxicity, 80% were found to have mild/moderate skin toxicity, while only 20% suffered from severe grades of skin toxicity. CONCLUSION: Gemcitabine in low-dose and long-duration infusion is a potent radiosensitizer with safer hematological toxicity and manageable local toxicities.


Assuntos
Carcinoma de Células Escamosas , Quimiorradioterapia , Desoxicitidina , Gencitabina , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Quimiorradioterapia/métodos , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Idoso , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Resultado do Tratamento , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/efeitos adversos , Esquema de Medicação , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/uso terapêutico , Estadiamento de Neoplasias
15.
J Med Chem ; 67(14): 12366-12385, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39007759

RESUMO

The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.


Assuntos
Proteína Quinase Ativada por DNA , Inibidores de Proteínas Quinases , Radiossensibilizantes , Humanos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/síntese química , Relação Estrutura-Atividade , Camundongos , Linhagem Celular Tumoral , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Imidazóis/farmacocinética , Piridonas/farmacologia , Piridonas/química , Piridonas/síntese química , Piridonas/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Ratos
16.
Anticancer Res ; 44(8): 3587-3591, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39060048

RESUMO

BACKGROUND/AIM: Acetyl glucose adducts (UTX-114, -115, and -116) were prepared from gefitinib, and their characteristics (e.g., anticancer activity, structural property) were analyzed. MATERIALS AND METHODS: Cytotoxicity and radiosensitizing properties of the UTX-114 family were examined using A431 cells. Supramolecular associations between the UTX-114 family compounds and the tyrosine kinase domain of epidermal growth factor receptor (EGFR-tyk) were also examined. The interactive analyses of the UTX-114 family compounds with EGFR-tyk were performed using docking simulation technique. RESULTS: The UTX-114 family showed a similar cytotoxicity as gefitinib, yielding IC50 values of 31.2 µM (gefitinib), 34.3 µM (UTX-114), 36.8 µM (UTX-115), and 39.4 µM (UTX-116). The EGFR-tyk inhibition ratios (IR) of UTX-114, -115, and -116 to gefitinib were 1.515, 0.983, and 0.551, respectively. The EGFR-tyk inhibitory activity of UTX-114 was higher than that of gefitinib. UTX-114 also showed the highest radiosensitizing activity among the tested compounds. UTX-114 expressed 1841 conformers (-8.989~15.718 kcal/mol) with the solvation free energy (dGW) of UTX-114 decreasing with increasing conformational energy, ranging between -354.955~ -260.815 kJ/mol. Interactive energies of gefitinib, UTX-114, -115, and -116 with EGFR-tyk were -123.640, -144.053, -120.830, and -124.658 kcal/mol, respectively. CONCLUSION: UTX-114 yielded the lowest interaction energy with EGFR-tyk among tested compounds. Given the association behavior between UTX-114 and EGFR-tyk, along with its other observed properties, UTX-114 appears to be a viable therapeutic possibility.


Assuntos
Receptores ErbB , Gefitinibe , Simulação de Acoplamento Molecular , Gefitinibe/farmacologia , Humanos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Glicosilação , Inibidores de Proteínas Quinases/farmacologia , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química
17.
Int J Nanomedicine ; 19: 6499-6513, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38946887

RESUMO

Purpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers. Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity. Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors. Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.


Assuntos
Nanopartículas , Terapia Fototérmica , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espécies Reativas de Oxigênio , Animais , Terapia Fototérmica/métodos , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Linhagem Celular Tumoral , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Camundongos , Indóis/farmacologia , Indóis/química , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Radiossensibilizantes/farmacologia , Radiossensibilizantes/química , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/radioterapia , Neoplasias/terapia , Neoplasias/metabolismo , Nanomedicina
18.
Cancer Med ; 13(13): e7332, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38967145

RESUMO

BACKGROUND: Radiotherapy (RT) is a widely utilized tumor treatment approach, while a significant obstacle in this treatment modality is the radioresistance exhibited by tumor cells. To enhance the effectiveness of RT, scientists have explored radiosensitization approaches, including the use of radiosensitizers and physical stimuli. Nevertheless, several approaches have exhibited disappointing results including adverse effects and limited efficacy. A safer and more effective method of radiosensitization involves low-intensity ultrasound (LIUS), which selectively targets tumor tissue and enhances the efficacy of radiation therapy. METHODS: This review summarized the tumor radioresistance reasons and explored LIUS potential radiosensitization mechanisms. Moreover, it covered diverse LIUS application strategies in radiosensitization, including the use of LIUS alone, ultrasound-targeted intravascular microbubble destruction, ultrasound-mediated targeted radiosensitizers delivery, and sonodynamic therapy. Lastly, the review presented the limitations and prospects of employing LIUS-RT combined therapy in clinical settings, emphasizing the need to connect research findings with practical applications. RESULTS AND CONCLUSION: LIUS employs cost-effective equipment to foster tumor radiosensitization, curtail radiation exposure, and elevate the quality of life for patients. This efficacy is attributed to LIUS's ability to utilize thermal, cavitation, and mechanical effects to overcome tumor cell resistance to RT. Multiple experimental analyses have underscored the effectiveness of LIUS in inducing tumor radiosensitization using diverse strategies. While initial studies have shown promising results, conducting more comprehensive clinical trials is crucial to confirm its safety and effectiveness in real-world situations.


Assuntos
Neoplasias , Radiossensibilizantes , Terapia por Ultrassom , Humanos , Neoplasias/radioterapia , Neoplasias/terapia , Radiossensibilizantes/uso terapêutico , Radiossensibilizantes/farmacologia , Terapia por Ultrassom/métodos , Terapia Combinada , Animais , Tolerância a Radiação , Ondas Ultrassônicas
19.
Chem Biol Interact ; 399: 111149, 2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-39032852

RESUMO

Rhabdomyosarcoma (RMS) represents one of the most lethal soft-tissue sarcomas in children. The toxic trace element arsenic has been reported to function as a radiosensitizer in sarcomas. To investigate the role of arsenic sulfide (As4S4) in enhancing radiation sensitization in RMS, this study was conducted to elucidate its underlying mechanism in radiotherapy. The combination of As4S4 and radiotherapy showed significant inhibition in RMS cells, as demonstrated by the cell counting kit-8 (CCK-8) assay and flow cytometry. Subsequently, we demonstrated for the first time that As4S4, as well as the knockdown of NFATc3 led to double-strand break (DSB) through increased expression of RAG1. In vivo experiment confirmed that co-treatment efficiently inhibited RMS growth. Furthermore, survival analysis of a clinical cohort consisting of 59 patients revealed a correlation between NFATc3 and RAG1 expression and overall survival (OS). Cox regression analysis also confirmed the independent prognostic significance of NFATc3 and RAG1.Taken together, As4S4 enhances radiosensitivity in RMS via activating NFATc3-RAG1 mediated DSB. NFATc3 and RAG1 are potential therapeutic targets. As4S4 will hopefully serve as a prospective radio-sensitizing agent for RMS.


Assuntos
Arsenicais , Quebras de DNA de Cadeia Dupla , Fatores de Transcrição NFATC , Tolerância a Radiação , Rabdomiossarcoma , Sulfetos , Humanos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/radioterapia , Rabdomiossarcoma/patologia , Rabdomiossarcoma/genética , Linhagem Celular Tumoral , Masculino , Feminino , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Animais , Tolerância a Radiação/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Camundongos , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Camundongos Nus , Criança , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Camundongos Endogâmicos BALB C
20.
J Exp Clin Cancer Res ; 43(1): 159, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840237

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. EXPERIMENTAL DESIGN: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. CONCLUSION: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.


Assuntos
Carcinoma de Células Renais , Reparo do DNA , Neoplasias Renais , Survivina , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Animais , Survivina/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Neoplasias Renais/patologia , Neoplasias Renais/radioterapia , Neoplasias Renais/tratamento farmacológico , Reparo do DNA/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Mitose/efeitos dos fármacos , Mitose/efeitos da radiação , Imidazóis/farmacologia , Dano ao DNA , Everolimo/farmacologia , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Lipossomos/farmacologia , Inibidores de MTOR/farmacologia , Inibidores de MTOR/uso terapêutico
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