ABSTRACT
Pancreatic ductal adenocarcinoma is a devastating disease characterized by an extreme resistance to current therapies, including immune checkpoint therapy. The limited success of immunotherapies can be attributed to a highly immunosuppressive pancreatic cancer microenvironment characterized by an extensive infiltration of immune suppressing myeloid cells. While there are several pathways through which myeloid cells contribute to immunosuppression, one important mechanism is the increased production of reactive oxygen species. Here, we evaluated the contribution of myeloperoxidase, a myeloid-lineage restricted enzyme and primary source of reactive oxygen species, to regulate immune checkpoint therapy response in preclinical pancreatic cancer models. We compared treatment outcome, immune composition and characterized myeloid cells using wild-type, myeloperoxidase-deficient, and myeloperoxidase inhibitor treated wild-type mice using established subcutaneous pancreatic cancer models. Loss of host myeloperoxidase and pharmacological inhibition of myeloperoxidase in combination with immune checkpoint therapy significantly delayed tumor growth. The tumor microenvironment and systemic immune landscape demonstrated significant decreases in myeloid cells, exhausted T cells and T regulatory cell subsets when myeloperoxidase was deficient. Loss of myeloperoxidase in isolated myeloid cell subsets from tumor-bearing mice resulted in decreased reactive oxygen species production and T cell suppression. These data suggest that myeloperoxidase contributes to an immunosuppressive microenvironment and immune checkpoint therapy resistance where myeloperoxidase inhibitors have the potential to enhance immunotherapy response. Repurposing myeloperoxidase specific inhibitors may provide a promising therapeutic strategy to expand therapeutic options for pancreatic cancer patients to include immunotherapies.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Humans , Mice , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Immunosuppression Therapy , Immunotherapy/methods , Myeloid Cells , Pancreatic Neoplasms/metabolism , Peroxidase/therapeutic use , Reactive Oxygen Species/therapeutic use , Tumor MicroenvironmentABSTRACT
BACKGROUND: Resistance can develop during treatment of advanced endometrial cancer (EC), leading to unsatisfactory results. Fanconi anemia complementation group D2 (Fancd2) has been shown to be closely related to drug resistance in cancer cells. Therefore, this study was designed to explore the correlation of Fancd2 with EC resistance and the mechanism of Fancd2. METHODS: Real-time quantitative PCR (RT-qPCR) was used to detect the expression of Fancd2 in EC tissues and cells. EC cells (Ishikawa) and paclitaxel-resistant EC cells (Ishikawa/TAX) were transfected to knock down Fancd2. In addition, the ferroptosis inhibitor Ferrostatin-1 was adopted to treat Ishikawa/TAX cells. The sensitivity of cancer cells to chemotherapeutic agents was observed via 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and inhibitory concentration (IC)50 was calculated. Reactive oxygen species (ROS) levels were measured by flow cytometry, the activity of malondialdehyde (MDA) and the levels of glutathione (GSH) and Fe2+ in cells were detected by corresponding kits, and protein expression of solute farrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was obtained through western blot. RESULTS: Compared with the normal tissues and endometrial epithelial cells, Fancd2 expression was significantly increased in EC tissues and Ishikawa cells, respectively. After knock-down of Fancd2, Ishikawa cells showed significantly increased sensitivity to chemotherapeutic agents. Besides, compared with Ishikawa cells, the levels of ROS, the activity of MDA, and the levels of GSH and Fe2+ were significantly decreased in Ishikawa/TAX cells, while the expression levels of SLC7A11 and GPX4 were significantly increased. Knock-down of Fancd2 significantly increased the ferroptosis levels in Ishikawa/TAX cells, but this effect could be reversed by Ferrostatin-1. CONCLUSION: Fancd2 increases drug resistance in EC cells by inhibiting the cellular ferroptosis pathway.
Subject(s)
Cyclohexylamines , Endometrial Neoplasms , Fanconi Anemia , Ferroptosis , Phenylenediamines , Female , Humans , Reactive Oxygen Species/therapeutic use , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/geneticsABSTRACT
Functional recovery following a spinal cord injury (SCI) is challenging. Traditional drug therapies focus on the suppression of immune responses; however, strategies for alleviating oxidative stress are lacking. Herein, we developed the zinc-organic framework (Zn@MOF)-based aggregation-induced emission-active nanozymes for accelerating recovery following SCI. A multifunctional Zn@MOF was modified with the aggregation-induced emission-active molecule 2-(4-azidobutyl)-6-(phenyl(4-(1,2,2-triphenylvinyl)phenyl)amino)-1H-phenalene-1,3-dione via a bioorthogonal reaction, and the resulting nanozymes were denoted as Zn@MOF-TPD. These nanozymes gradually released gallic acid and zinc ions (Zn2+) at the SCI site. The released gallic acid, a scavenger of reactive oxygen species (ROS), promoted antioxidation and alleviated inflammation, re-establishing the balance between ROS production and the antioxidant defense system. The released Zn2+ ions inhibited the activity of matrix metalloproteinase 9 (MMP-9) to facilitate the regeneration of neurons via the ROS-mediated NF-κB pathway following secondary SCI. In addition, Zn@MOF-TPD protected neurons and myelin sheaths against trauma, inhibited glial scar formation, and promoted the proliferation and differentiation of neural stem cells, thereby facilitating the repair of neurons and injured spinal cord tissue and promoting functional recovery in rats with contusive SCI. Altogether, this study suggests that Zn@MOF-TPD nanozymes possess a potential for alleviating oxidative stress-mediated pathophysiological damage and promoting motor recovery following SCI.
Subject(s)
Spinal Cord Injuries , Zinc , Rats , Animals , Zinc/therapeutic use , Reactive Oxygen Species/therapeutic use , Spinal Cord Injuries/drug therapy , Spinal Cord , Gallic Acid/therapeutic use , IonsABSTRACT
We report a facile stimuli-responsive strategy to generate reactive oxygen and nitrogen species (ROS and RNS) in the biological milieu from a photocleavable water-soluble block copolymer under visible light irradiation (427 nm, 2.25 mW/cm2). An anthraquinone-based water-soluble polymeric nitric oxide (NO) donor (BCPx-NO) is synthesized, which exhibits NO release in the range of 40-65 µM within 10 h of photoirradiation with a half-life of 30-103 min. Additionally, BCPx-NO produces peroxynitrite (ONOO-) and singlet oxygen (1O2) under photoirradiation. To understand the mechanism of NO release and photolysis of the functional group under blue light, we prepared a small-molecule anthraquinone-based N-nitrosamine (NOD). The cellular investigation of the effect of spatiotemporally controlled ONOO- and 1O2 generation from the NO donor polymeric nanoparticles in a triple negative breast adenocarcinoma (MDA-MB-231) under visible light irradiation (white light, 5.83 mW/cm2; total dose 31.5 J/cm2) showed an IC50 of 0.6 mg/mL. The stimuli-responsive strategy using a photolabile water-soluble block copolymer employed to generate ROS and RNS in a biological setting widens the horizon for their potential in cancer therapy.
Subject(s)
Neoplasms , Peroxynitrous Acid , Humans , Peroxynitrous Acid/therapeutic use , Reactive Oxygen Species/therapeutic use , Polymers/therapeutic use , Reactive Nitrogen Species/therapeutic use , Light , Oxygen/therapeutic use , Nitric Oxide/therapeutic use , Anthraquinones/therapeutic use , Neoplasms/drug therapyABSTRACT
Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
Subject(s)
Alzheimer Disease , Mitochondrial Diseases , Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/therapy , Neurodegenerative Diseases/drug therapy , Mitochondria , Reactive Oxygen Species/therapeutic use , Alzheimer Disease/pathology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapyABSTRACT
BACKGROUND: Genomic diagnostic testing is necessary to guide optimal treatment for non-small cell lung cancer (NSCLC) patients. The proportion of NSCLC patients whose treatment was selected based on genomic testing is still unknown in many countries or needs further improvement. This survey aimed to assess perception of genomic testing and targeted therapy for NSCLC in clinical pathologists and physicians across China. METHODS: The web-based survey was conducted with 150 clinical pathologists and 450 physicians from oncology, respiratory and thoracic surgery departments from May to September 2020, across 135 cities in China. The participants had >5 years of clinical experience in genomic testing, diagnosis or treatment of NSCLC. RESULTS: Clinical pathologists reported capability of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS-1) testing as 95.3%, 94.7%, and 84.7%, respectively, but only 81.9%, 75.5%, and 65.6% of physicians believed that the pathology department of the hospital is capable of performing the testing. The proportions of sending out specimens for testing were 21.0% and 49.7% as reported from clinical pathologists and physicians, respectively. Testing for EGFR mutation was recommended by physicians most often, followed by ALK and ROS-1 rearrangement. As first-line treatment, among the newly diagnosed patients with EGFR mutation, 77% received tyrosine kinase inhibitors (TKIs) therapy (49% treated with gefitinib); among patients with ALK rearrangement, 71% received TKI (64% treated with crizotinib); among patients with ROS-1 fusion, 65% received TKI (88% treated with crizotinib). CONCLUSIONS: The improvement of the non-tertiary hospital pathology departments' detection capabilities and the physicians' awareness are needed for enhancing the rate of genomic testing and targeted therapy in NSCLC patients in China.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Physicians , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Pathologists , Reactive Oxygen Species/therapeutic use , ErbB Receptors/genetics , Genetic TestingABSTRACT
La revolución que se produjo en las áreas de la salud en el mundo durante el siglo XX, o lo que se ha dado en llamar la transición epidemiológica, ha hecho que la población mundial envejezca y con ello las enfermedades crónicas no trasmisibles, aparezcan cada vez con mayor frecuencia. Entre estas, las enfermedades cardiovasculares, específicamente las del corazón, son las de mayor incidencia. El oxígeno es esencial para la vida, pero posee una paradoja en los organismos que lo utilizan. Este elemento desempeña una función importante como aceptor final de electrones durante la respiración celular, pero también constituye el punto de partida para un tipo de daño celular conocido como estrés oxidativo. La experiencia clínica y los estudios prospectivos constituyen una herramienta de gran utilidad, lo cual ha permitido establecer una asociación entre el estrés oxidativo y las enfermedades cardiovasculares, se plantea que este es un evento precoz en el desarrollo de la disfunción endotelial y de la subsecuente afección cardiovascular. En el presente trabajo se realizó una revisión bibliográfica actualizada sobre la función del estrés oxidativo y las especies reactivas de oxígeno en la fisiopatología de estas enfermedades.
Changes occurred in health areas at world level during XX Century, or the so called epidemiologic transition, lead to world population aging, and thus the non-communicable chronic diseases, appear with more and more frequency. Among them, cardiovascular diseases, specifically those of heart, have the greater incidence. Oxygen is essential for life, but it has a paradox in organisms used it. This element has a significant role as final acceptor of electrons during cellular breathing, but also is start point of cellular damage known as oxidative stress. Clinical experience and prospective studies is a very useful tool, which has allowed us to establish an association between oxidative stress and cardiovascular diseases. We propose that this is an early event in development of endothelial dysfunction and the subsequent cardiovascular affection. In present paper we made a updated bibliographic review on role of oxidative stress, and the reactive species of oxygen in physiopathology of these diseases.