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Frontiers in Oncology 2020Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially... (Review)
Review
Ferroptosis is a newly described type of programmed cell death and intensively related to both maintaining homeostasis and the development of diseases, especially cancers. Inducing ferroptosis leads to mitochondrial dysfunction and toxic lipid peroxidation in cells, which plays a pivotal role in suppressing cancer growth and progression. Here, we reviewed the existing studies about the molecular mechanisms of ferroptosis involved in different antitumor treatments, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy. We focused in particular on the distinct combinatorial therapeutic effects such as the synergistic sensitization effect and the drug-resistance reversal achieved when using ferroptosis inducers with conventional cancer therapy. Finally, we discussed the challenges and opportunities in clinical applications of ferroptosis. The application of nanotechnolgy and other novel technologies may provide a new direction in ferroptosis-driven cancer therapies.
PubMed: 33102227
DOI: 10.3389/fonc.2020.571127 -
Advanced Science (Weinheim,... Nov 2023Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase...
Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H ) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H , both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H together with radiotherapy-causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL-tailored content of H and Ca strengthens radiotherapy-induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti-tumor adaptive immunity. Meanwhile, macrophages in the CCL-treated tumors are polarized from pro-tumor M2 to anti-tumor M1 under X-ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca content. Therefore, multi-directional regulation of the intra/extra tumor cell pH/calcium by simple nano-preparation would provide a powerful way to improve the efficacy of radio-immunotherapy.
Topics: Humans; Calcium; Hydrogen-Ion Concentration; Neoplasms; Immunotherapy; Homeostasis; Tumor Microenvironment
PubMed: 37740415
DOI: 10.1002/advs.202304092 -
International Journal of Molecular... Jul 2023Single cell biology has revealed that solid tumors and tumor-derived cell lines typically contain subpopulations of cancer cells that are readily distinguishable from... (Review)
Review
Single cell biology has revealed that solid tumors and tumor-derived cell lines typically contain subpopulations of cancer cells that are readily distinguishable from the bulk of cancer cells by virtue of their enormous size. Such cells with a highly enlarged nucleus, multiple nuclei, and/or multiple micronuclei are often referred to as polyploid giant cancer cells (PGCCs), and may exhibit features of senescence. PGCCs may enter a dormant phase (active sleep) after they are formed, but a subset remain viable, secrete growth promoting factors, and can give rise to therapy resistant and tumor repopulating progeny. Here we will briefly discuss the prevalence and prognostic value of PGCCs across different cancer types, the current understanding of the mechanisms of their formation and fate, and possible reasons why these tumor repopulating "monsters" continue to be ignored in most cancer therapy-related preclinical studies. In addition to PGCCs, other subpopulations of cancer cells within a solid tumor (such as oncogenic caspase 3-activated cancer cells and drug-tolerant persister cancer cells) can also contribute to therapy resistance and pose major challenges to the delivery of cancer therapy.
Topics: Humans; Neoplasms; Giant Cells; Polyploidy
PubMed: 37511291
DOI: 10.3390/ijms241411534 -
Current Topics in Medicinal Chemistry 2022Alzheimer's disease (AD) is a severe progressive neurodegenerative condition that shows misfolding and aggregation of proteins contributing to a decline in cognitive... (Review)
Review
Alzheimer's disease (AD) is a severe progressive neurodegenerative condition that shows misfolding and aggregation of proteins contributing to a decline in cognitive function involving multiple behavioral, neuropsychological, and cognitive domains. Multiple epi (genetic) changes and environmental agents have been shown to play an active role in ER stress induction. Neurodegeneration due to endoplasmic reticulum (ER) stress is considered one of the major underlying causes of AD. ER stress may affect essential cellular functions related to biosynthesis, assembly, folding, and post-translational modification of proteins leading to neuronal inflammation to promote AD pathology. Treatment with phytochemicals has been shown to delay the onset and disease progression and improve the well-being of patients by targeting multiple signaling pathways in AD. Phytochemical's protective effect against neuronal damage in AD pathology may be associated with the reversal of ER stress and unfolding protein response by enhancing the antioxidant and anti-inflammatory properties of the neuronal cells. Hence, pharmacological interventions using phytochemicals can be a potential strategy to reverse ER stress and improve AD management. Towards this, the present review discusses the role of phytochemicals in preventing ER stress in the pathology of AD.
Topics: Humans; Endoplasmic Reticulum Stress; Alzheimer Disease; Neurons; Signal Transduction; Phytochemicals
PubMed: 35761490
DOI: 10.2174/1568026622666220624155357 -
Frontiers in Immunology 2020Sepsis is a leading cause of death in intensive care units and survivors develop prolonged immunosuppression and a high incidence of recurrent infections. No definitive... (Review)
Review
Sepsis is a leading cause of death in intensive care units and survivors develop prolonged immunosuppression and a high incidence of recurrent infections. No definitive therapy exists to treat sepsis and physicians rely on supportive care including antibiotics, intravenous fluids, and vasopressors. With the rising incidence of antibiotic resistant microbes, it is becoming increasingly critical to discover novel therapeutics. Sepsis-induced leukocyte dysfunction and immunosuppression is recognized as an important contributor towards increased morbidity and mortality. Pre-clinical and clinical studies show that specific cell surface inhibitory immune checkpoint receptors and ligands including PD-1, PD-L1, CTLA4, BTLA, TIM3, OX40, and 2B4 play important roles in the pathophysiology of sepsis by mediating a fine balance between host immune competency and immunosuppression. Pre-clinical studies targeting the inhibitory effects of these immune checkpoints have demonstrated reversal of leukocyte dysfunction and improved host resistance of infection. Measurement of immune checkpoint expression on peripheral blood leukocytes may serve as a means of stratifying patients to direct individualized therapy. This review focuses on advances in our understanding of the role of immune checkpoints in the host response to infections, and the potential clinical application of therapeutics targeting the inhibitory immune checkpoint pathways for the management of septic patients.
Topics: Gene Expression Regulation; Humans; Immune Checkpoint Proteins; Immune Tolerance; Leukocytes; Sepsis
PubMed: 33613563
DOI: 10.3389/fimmu.2020.624272 -
Cellular and Molecular Life Sciences :... Jan 2020The compaction of DNA and the continuous action of DNA transactions, including transcription and DNA replication, create complex DNA topologies that require Type IIA... (Review)
Review
The compaction of DNA and the continuous action of DNA transactions, including transcription and DNA replication, create complex DNA topologies that require Type IIA Topoisomerases, which resolve DNA topological strain and control genome dynamics. The human TOP2 enzymes catalyze their reactions via formation of a reversible covalent enzyme DNA-protein crosslink, the TOP2 cleavage complex (TOP2cc). Spurious interactions of TOP2 with DNA damage, environmental toxicants and chemotherapeutic "poisons" perturbs the TOP2 reaction cycle, leading to an accumulation of DNA-protein crosslinks, and ultimately, genomic instability and cell death. Emerging evidence shows that TOP2-DNA protein crosslink (DPC) repair entails multiple strand break repair activities, such as removal of the poisoned TOP2 protein and rejoining of the DNA ends through homologous recombination (HR) or non-homologous end joining (NHEJ). Herein, we discuss the molecular mechanisms of TOP2-DPC resolution, with specific emphasis on the recently uncovered ZATT-licensed TDP2-catalyzed TOP2-DPC reversal mechanism.
Topics: Aminoacyltransferases; Animals; DNA; DNA Breaks; DNA Repair; DNA Topoisomerases, Type II; Humans; Poly-ADP-Ribose Binding Proteins; Protein Conformation; Sumoylation; Transcription Factors
PubMed: 31728578
DOI: 10.1007/s00018-019-03367-z -
Cell Death Discovery Jul 2023Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific...
Lack of dystrophin expression is the underlying genetic basis for Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with an enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports the excessive accumulation of fibroadipogenic progenitors (FAPs), leading to increased fibrosis. Unexpectedly, the extent of damage and degeneration in juvenile D2-mdx muscle is significantly reduced in adults, and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance regenerative myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder B10-mdx model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with juvenile D2-mdx FAPs reduces their fusion efficacy. Wild-type juvenile D2 mice also manifest regenerative myogenic deficit and glucocorticoid treatment improves their muscle regeneration. Our findings indicate that aberrant stromal cell responses contribute to poor regenerative myogenesis and greater muscle degeneration in juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx muscle, identifying these responses as a potential therapeutic target for the treatment of DMD.
PubMed: 37402716
DOI: 10.1038/s41420-023-01503-0 -
Pakistan Journal of Biological Sciences... Jan 2023The DNA is constantly under attack from endogenous and exogenous damaging agents. The damaged DNA must be repaired quickly to avoid genomic instability and to prevent... (Review)
Review
The DNA is constantly under attack from endogenous and exogenous damaging agents. The damaged DNA must be repaired quickly to avoid genomic instability and to prevent the occurrence of a malignant transformation. Once a lesion is detected, the DNA repair mechanism initiates and replaces the structurally altered base or any other abnormality. The cell repair mechanisms include direct reversal, excision repair (base excision repair [BER] and nucleotide excision repair [NER]), mismatch repair (MMR), homologous recombination repair (HR) and non-homologous end joining (NHEJ). Unrepaired DNA could lead to mutation, cell death or cancer. This review will discuss how the defects in DNA repair play a vital role in cancer initiation, development and progression.
Topics: Humans; DNA Repair; DNA Damage; Neoplasms; DNA; DNA Repair-Deficiency Disorders
PubMed: 37129201
DOI: 10.3923/pjbs.2023.15.22 -
Frontiers in Pharmacology 2023Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent...
Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent years, researchers have focused on understanding the mechanisms of multidrug resistance (MDR) in cancer cells and have identified the overexpression of ATP-binding cassette (ABC) transporters, including ABCC1/MRP1 and ABCC10/MRP7, as a key factor in the development of MDR. In this study, we aimed to investigate whether three drugs (sertraline, fluoxetine, and citalopram) from the selective serotonin reuptake inhibitor (SSRI) family, commonly used as antidepressants, could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse MDR in cancer cells. Using a combination of predictions and validations, we analyzed the interaction of MRP1 and MRP7 with the drugs and evaluated their ability to hinder cell resistance. We used computational tools to identify and analyze the binding site of these three molecules and determine their binding energy. Subsequently, we conducted experimental assays to assess cell viability when treated with various standard chemotherapies, both with and without the presence of SSRI inhibitors. Our results show that all three SSRI drugs exhibited inhibitory/reversal effects in the presence of chemotherapies on both MRP1-overexpressed cells and MRP7-overexpressed cells, suggesting that these medications have the potential to be repurposed to target MDR in cancer cells. These findings may open the door to using FDA-approved medications in combination therapy protocols to treat highly resistant malignancies and improve the efficacy of chemotherapy treatment. Our research highlights the importance of investigating and repurposing existing drugs to overcome MDR in cancer treatment.
PubMed: 38026953
DOI: 10.3389/fphar.2023.1290255 -
Cell Death and Differentiation Mar 2023Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells...
Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we developed a reporter system, mCasExpress, to track mammalian cells that survive executioner caspase activation. We demonstrate that anastatic ovarian cancer cells acquire enhanced migration following their transient exposure to apoptotic stimulus TRAIL or Paclitaxel. Moreover, anastatic cancer cells secrete more pro-angiogenic factors that enable tumor angiogenesis, growth and metastasis. Mechanistically, we demonstrate that activation of p38 MAPK, which occurs in a caspase-dependent manner in response to apoptotic stress to promote anastasis, persists at a higher level in anastatic cancer cells even after removal of apoptotic stimuli. Importantly, p38 is essential for the elevated migratory and angiogenic capacity in the anastatic cells. Our work unveils anastasis as a potential driver of tumor angiogenesis and metastasis.
Topics: Animals; Humans; Female; p38 Mitogen-Activated Protein Kinases; Cell Death Reversal; Apoptosis; Caspases; Ovarian Neoplasms; Mammals
PubMed: 36447048
DOI: 10.1038/s41418-022-01081-1