RESUMEN
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.
Asunto(s)
Apoptosis , Neoplasias Colorrectales , Flavanonas , Janus Quinasa 2 , Ratones Endogámicos BALB C , Tolerancia a Radiación , Factor de Transcripción STAT3 , Transducción de Señal , Janus Quinasa 2/metabolismo , Flavanonas/farmacología , Flavanonas/química , Flavanonas/uso terapéutico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Ratones , Tolerancia a Radiación/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/químicaRESUMEN
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.
Asunto(s)
Quimioradioterapia , Sistemas de Liberación de Medicamentos , Nanomedicina , Neoplasias , Humanos , Animales , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/químicaAsunto(s)
Tolerancia a Radiación , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia , Femenino , Reparación del ADN , Daño del ADN , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ciclo Celular , Hipertermia Inducida/métodos , Pronóstico , Sistemas de Liberación de Medicamentos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéuticoRESUMEN
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.
Asunto(s)
Carcinoma de Células Escamosas , Quimioradioterapia , Desoxicitidina , Gemcitabina , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Quimioradioterapia/métodos , Quimioradioterapia/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Anciano , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Resultado del Tratamiento , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Esquema de Medicación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Estadificación de NeoplasiasRESUMEN
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.
Asunto(s)
Neoplasias , Fármacos Sensibilizantes a Radiaciones , Terapia por Ultrasonido , Humanos , Neoplasias/radioterapia , Neoplasias/terapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/farmacología , Terapia por Ultrasonido/métodos , Terapia Combinada , Animales , Tolerancia a Radiación , Ondas UltrasónicasRESUMEN
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.
Asunto(s)
Arsenicales , Roturas del ADN de Doble Cadena , Factores de Transcripción NFATC , Tolerancia a Radiación , Rabdomiosarcoma , Sulfuros , Humanos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Sulfuros/farmacología , Sulfuros/uso terapéutico , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/radioterapia , Rabdomiosarcoma/patología , Rabdomiosarcoma/genética , Línea Celular Tumoral , Masculino , Femenino , Arsenicales/farmacología , Arsenicales/uso terapéutico , Animales , Tolerancia a Radiación/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Ratones , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Ratones Desnudos , Niño , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ratones Endogámicos BALB CRESUMEN
Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment.
Asunto(s)
Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Neoplasias Pulmonares , Ratones Desnudos , Quinolinas , Fármacos Sensibilizantes a Radiaciones , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Quinolinas/farmacología , Quinolinas/uso terapéutico , Apoptosis/efectos de los fármacos , Ratones , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Bases de Schiff/farmacología , Bases de Schiff/uso terapéutico , Indoles/farmacología , Indoles/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Tolerancia a Radiación/efectos de los fármacosRESUMEN
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.
Asunto(s)
Carcinoma de Células Renales , Reparación del ADN , Neoplasias Renales , Survivin , Serina-Treonina Quinasas TOR , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/radioterapia , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Animales , Survivin/metabolismo , Humanos , Ratones , Línea Celular Tumoral , Neoplasias Renales/patología , Neoplasias Renales/radioterapia , Neoplasias Renales/tratamiento farmacológico , Reparación del ADN/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Mitosis/efectos de los fármacos , Mitosis/efectos de la radiación , Imidazoles/farmacología , Daño del ADN , Everolimus/farmacología , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Liposomas/farmacología , Inhibidores mTOR/farmacología , Inhibidores mTOR/uso terapéuticoRESUMEN
Radiotherapy is an essential component of the treatment regimens for many cancer patients. Despite recent technological advancements to improve dose delivery techniques, the dose escalation required to enhance tumor control is limited due to the inevitable toxicity to the surrounding healthy tissue. Therefore, the local enhancement of dosing in tumor sites can provide the necessary means to improve the treatment modality. In recent years, the emergence of nanotechnology has facilitated a unique opportunity to increase the efficacy of radiotherapy treatment. The application of high-atomic-number (Z) nanoparticles (NPs) can augment the effects of radiotherapy by increasing the sensitivity of cells to radiation. High-Z NPs can inherently act as radiosensitizers as well as serve as targeted delivery vehicles for radiosensitizing agents. In this work, the therapeutic benefits of high-Z NPs as radiosensitizers, such as their tumor-targeting capabilities and their mechanisms of sensitization, are discussed. Preclinical data supporting their application in radiotherapy treatment as well as the status of their clinical translation will be presented.
Asunto(s)
Nanopartículas , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Nanopartículas/química , Nanopartículas/uso terapéutico , Animales , Radioterapia/métodosAsunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Tolerancia a Radiación , Humanos , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/patología , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Hipoxia Tumoral/efectos de la radiación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Hipoxia de la CélulaRESUMEN
We studied the antitumor activity of the combined use of local proton irradiation in two modes (10 and 31 Gy) with preliminary intra-tumoral injection of two types of bismuth nanoparticles differing in surface coating: coated with the amphiphilic molecule Pluronic-F127 or Silane-PEG (5 kDa)-COOH polymer. Nanoparticles were used in doses of 0.75 and 1.5 mg/mouse. In two independent series on experimental tumor model (solid Ehrlich carcinoma), bismuth nanoparticles of both modifications injected directly into the tumor enhanced the antitumor effects of proton therapy. Moreover, the radiosensitizing effect of bismuth nanoparticles administered via this route increased with the increasing the doses of nanoparticles and the doses of radiation exposure. In our opinion, these promising data obtained for the first time extend the possibilities of treating malignant neoplasms.
Asunto(s)
Bismuto , Carcinoma de Ehrlich , Poloxámero , Terapia de Protones , Carcinoma de Ehrlich/radioterapia , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/patología , Animales , Bismuto/uso terapéutico , Bismuto/química , Ratones , Terapia de Protones/métodos , Poloxámero/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/farmacología , Polietilenglicoles/química , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Nanopartículas/química , FemeninoRESUMEN
In the progression of X-ray-based radiotherapy for the treatment of cancer, the incorporation of nanoparticles (NPs) has a transformative impact. This study investigates the potential of NPs, particularly those comprised of high atomic number elements, as radiosensitizers. This aims to optimize localized radiation doses within tumors, thereby maximizing therapeutic efficacy while preserving surrounding tissues. The multifaceted applications of NPs in radiotherapy encompass collaborative interactions with chemotherapeutic, immunotherapeutic, and targeted pharmaceuticals, along with contributions to photodynamic/photothermal therapy, imaging enhancement, and the integration of artificial intelligence technology. Despite promising preclinical outcomes, the paper acknowledges challenges in the clinical translation of these findings. The conclusion maintains an optimistic stance, emphasizing ongoing trials and technological advancements that bolster personalized treatment approaches. The paper advocates for continuous research and clinical validation, envisioning the integration of NPs as a revolutionary paradigm in cancer therapy, ultimately enhancing patient outcomes.
Asunto(s)
Nanopartículas Multifuncionales , Humanos , Rayos X , Nanopartículas Multifuncionales/química , Neoplasias/terapia , Neoplasias/diagnóstico por imagen , Animales , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/uso terapéuticoRESUMEN
Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions on ferroptosis, contemplating the plausibility of using ferroptosis inducers as clinical radiosensitizers. Furthermore, we dive into the prospects of drug repurposing in the domain of ferroptosis inducers and radiosensitizers. Lastly, the potential adverse effects of ferroptosis inducers on normal tissue were discussed in detail. This review will provide an important framework for subsequent ferroptosis research, ascertaining the feasibility of ferroptosis inducers as clinical radiosensitizers.
Asunto(s)
Ferroptosis , Oncología por Radiación , Fármacos Sensibilizantes a Radiaciones , Muerte Celular Regulada , Humanos , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Muerte Celular , HipoxiaRESUMEN
Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (â¢OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.
Asunto(s)
Nanopartículas , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Neoplasias/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Apoptosis , Línea Celular Tumoral , Microambiente Tumoral , Peróxido de HidrógenoRESUMEN
Radiotherapy is a mainstay treatment used in clinics for locoregional therapy, although it still represents a great challenge to improve the sensitivity and accuracy of radiotherapy for tumors. Here, we report the conjugated polymer, polydiiododiacetylene (PIDA), with an iodine content of 84 wt %, as a highly effective computed tomography (CT) contrast agent and tumor microenvironment-responsive radiosensitizer. PIDA exhibited several key properties that contribute to the improvement of precision radiotherapy. The integrated PIDA nanofibers confined within the tumor envelope demonstrated amplified CT intensity and prolonged retention, providing an accurate calculation of dose distribution and precise radiation delivery for CT image-guided radiotherapy. Therefore, our strategy pioneers PIDA nanofibers as a bridge to cleverly connect a fiducial marker to guide accurate radiotherapy and a radiosensitizer to improve tumor sensitivity, thereby minimizing potential damage to surrounding tissues and facilitating on-demand therapeutic intervention in tumors.
Asunto(s)
Nanofibras , Neoplasias , Polímero Poliacetilénico , Fármacos Sensibilizantes a Radiaciones , Radioterapia Guiada por Imagen , Humanos , Carbono , Microambiente Tumoral , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéuticoRESUMEN
Radiotherapy is one of the most commonly used cancer therapies with many benefits including low toxicity to healthy tissues. However, a major problem in radiotherapy is cancer radioresistance. To enhance the effect of this kind of therapy several approaches have been proposed such as the use of radiosensitizers. A combined treatment of radiotherapy and radiosensitizing drugs leads to a greater effect on cancer cells than anticipated from the addition of both responses (synergism). In this study, high-definition FT-IR imaging was applied to follow lipid accumulation in prostate cancer cells as a response to X-ray irradiation, radiosensitizing drugs, and a combined treatment of X-rays and the drugs. Lipid accumulation induced in the cells by an increasing X-ray dose and the presence of the drugs was analyzed using Principal Component Analysis and lipid staining. Finally, the synergistic effect of the combined therapy (X-rays and radiosensitizers) was confirmed by calculations of the integral intensity of the 2850 cm-1 band.
Asunto(s)
Neoplasias de la Próstata , Fármacos Sensibilizantes a Radiaciones , Masculino , Humanos , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Línea Celular Tumoral , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Lípidos/uso terapéuticoRESUMEN
The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo-radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer-40 (denoted as IRnR-40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near-infrared fluorescence (NIR-II FL) imaging-guided safe-dose synergetic chemo-radiotherapy. The high concentration of matrix metalloproteinase-9 (MMP-9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR-40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real-time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)-mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR-40 is believed to be the first attempt to achieve efficient NIR-II FL imaging-guided safe-dose chemo-radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.
Asunto(s)
Artritis Reumatoide , Cisplatino , Verde de Indocianina , Imagen Óptica , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/tratamiento farmacológico , Animales , Verde de Indocianina/administración & dosificación , Ratones , Imagen Óptica/métodos , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Modelos Animales de Enfermedad , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Humanos , Quimioradioterapia/métodosRESUMEN
Cancer cells can upregulate the MYC expression to repair the radiotherapy-triggered DNA damage, aggravating therapeutic resistance and tumor immunosuppression. Epigenetic treatment targeting the MYC-transcriptional abnormality may intensively solve this clinical problem. Herein, 5-Aza (a DNA methyltransferase inhibitor) and ITF-2357 (a histone deacetylase inhibitor) are engineered into a tungsten-based nano-radiosensitizer (PWAI), to suppress MYC rising and awaken robust radiotherapeutic antitumor immunity. Individual 5-Aza depletes MYC expression but cannot efficiently awaken radiotherapeutic immunity. This drawback can be overcome by the addition of ITF-2357, which triggers cancer cellular type I interferon (IFN-I) signaling. Coupling 5-Aza with ITF-2357 ensures that PWAI does not evoke the treated model with high MYC-related immune resistance while amplifying the radiotherapeutic tumor killing, and more importantly promotes the generation of IFN-I signal-related proteins involving IFN-α and IFN-ß. Unlike the radiation treatment alone, PWAI-triggered immuno-radiotherapy remarkably enhances antitumor immune responses involving the tumor antigen presentation by dendritic cells, and improves intratumoral recruitment of cytotoxic T lymphocytes and their memory-phenotype formation in 4T1 tumor-bearing mice. Downgrading the radiotherapy-induced MYC overexpression via the dual-epigenetic reprogramming strategy may elicit a robust immuno-radiotherapy.
Asunto(s)
Epigénesis Genética , Inmunoterapia , Proteínas Proto-Oncogénicas c-myc , Fármacos Sensibilizantes a Radiaciones , Animales , Humanos , Ratones , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Epigénesis Genética/efectos de los fármacos , Terapia de Inmunosupresión/métodos , Inmunoterapia/métodos , Interferón Tipo I/metabolismo , Nanopartículas/química , Neoplasias/terapia , Neoplasias/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Metilasas de Modificación del ADN/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéuticoRESUMEN
Background: Radiotherapy is a widely used clinical tool for tumor treatment but can cause systemic toxicity if excessive radiation is administered. Although numerous nanoparticles have been developed as radiosensitizers to reduce the required dose of X-ray irradiation, they often have limitations, such as passive reliance on radiation-induced apoptosis in tumors, and little consider the unique tumor microenvironment that contributes radiotherapy resistance. Methods: In this study, we developed and characterized a novel self-assembled nanoparticle containing dysprosium ion and manganese ion (Dy/Mn-P). We systematically investigated the potential of Dy/Mn-P nanoparticles (NPs) as a reactive oxygen species (ROS) amplifier and radiosensitizer to enhance radiation therapy and modulate the tumor microenvironment at the cellular level. Additionally, we evaluated the effect of Dy/Mn-P on the stimulator of interferon genes (STING), an innate immune signaling pathway. Results: Physicochemical analysis demonstrated the prepared Dy/Mn-P NPs exhibited excellent dispersibility and stability, and degraded rapidly at lower pH values. Furthermore, Dy/Mn-P was internalized by cells and exhibited selective toxicity towards tumor cells compared to normal cells. Our findings also revealed that Dy/Mn-P NPs improved the tumor microenvironment and significantly increased ROS generation under ionizing radiation, resulting in a ~70% increase in ROS levels compared to radiation therapy alone. This enhanced ROS generation inhibited ~92% of cell clone formation and greatly contributed to cytoplasmic DNA exposure. Subsequently, the activation of the STING pathway was observed, leading to the secretion of pro-inflammatory immune factors and maturation of dendritic cells (DCs). Conclusion: Our study demonstrates that Dy/Mn-P NPs can potentiate tumor radiotherapy by improving the tumor microenvironment and increasing endogenous ROS levels within the tumor. Furthermore, Dy/Mn-P can amplify the activation of the STING pathway during radiotherapy, thereby triggering an anti-tumor immune response. This novel approach has the potential to expand the application of radiotherapy in tumor treatment.
Asunto(s)
Nanopartículas , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Especies Reactivas de Oxígeno/metabolismo , Microambiente Tumoral , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Nanopartículas/química , Concentración de Iones de HidrógenoRESUMEN
Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented radiation-induced killing of M12 cells at concentrations ≥100 nmol/L, and a minimum of 16 hours exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and 7 hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy × 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; P = 0.0015) and M15 (50%; P = 0.03), while more limited effects were seen in M27 (16%, P = 0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.