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Doxorubicin—An Agent with Multiple Mechanisms of Anticancer Activity
Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, the precise mechanisms of DOX’s action are not fully understood. Emerging evidence points to the pleiotropic anticancer activity of DOX, including its contribution to DNA damage, reactive oxygen species (ROS) production, apoptosis, senescence, autophagy, ferroptosis, and pyroptosis induction, as well as its immunomodulatory role. This review aims to collect information on the anticancer mechanisms of DOX as well as its influence on anti-tumor immune response, providing a rationale behind the importance of DOX in modern cancer therapy.
Journal Article
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21 WAF1/CIP1 and p16 INK4A /pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
Journal Article
The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma
The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.
Journal Article
Application Development on the Nexys 4 DDR Platform: Techniques And Implementations
The article explores the application of digital circuits, such as logic gates, logic functions, flip-flop, and automata, using the Nexys 4 DDR platform from Xilinx and the Vivado software. The Nexys 4 DDR, featuring the Artix-7 FPGA, provides a robust environment for designing and testing digital systems. It allows for efficient implementation of various digital functions through hardware programming and simulation. The use of Vivado software eases the creation, simulation, and deployment of custom digital circuits, highlighting the versatility and power of FPGA technology in real-world applications. This paper highlights key principles, practical implementations, and design considerations involved in using these tools for digital circuit applications.
Journal Article
C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review
The G4C2 repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While healthy individuals have fewer than 30 repeats, affected patients may carry hundreds to thousands. This expansion accounts for approximately 40% of familial ALS and 25% of familial FTD cases, and between 5 and 10% cases of sporadic ALS and FTD. Three overlapping pathological mechanisms have been proposed for the C9orf72 expansion: loss of function due to protein deficiency, gain of function through RNA foci, and the production of toxic dipeptide repeat proteins (DPRs) via repeat-associated non-ATG (RAN) translation. This systematic review investigates the role of DNA damage in C9orf72 -related ALS-FTD. Analysis of twelve peer-reviewed studies showed that C9orf72 repeat expansions and DPRs compromise genome stability across four experimental models: human cell lines, induced pluripotent stem cell-derived neurons, rodent neurons, and postmortem tissue. We identified four mechanisms underlying DNA damage accumulation: disruption of the ATM pathway, impairment of DNA repair efficiency, formation of R-loops, and mitochondrial dysfunction with oxidative stress. In addition, several consequences of DNA damage were identified, including misrepair-mediated repeat expansion and activation of STING pathway. These findings highlight the key role of DNA damage in C9orf72-related pathology. Consistent with this, targeting DNA damage response factors extended lifespan and improved motor function in mouse models. This review highlights the contribution of DNA damage to C9orf72 pathology and suggest new therapeutic avenues, including personalized approaches based on genetic background.
Journal Article
Design, Synthesis, and Biological Evaluation of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase for the Efficient Treatment of Cancer
Ataxia telangiectasia mutated and Rad3-related (ATR), a vital member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, plays a critical role in the DNA damage response (DDR). Tumor cells with a loss of DDR function or defects in the ataxia telangiectasia mutated (ATM) gene are generally more dependent on ATR for survival, suggesting that ATR is an attractive anticancer drug target based on its synthetic lethality. Herein, we present a potent and highly selective ATR inhibitor, ZH-12 (IC50 = 0.0068 μM). It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR inhibitor based on the principle of synthetic lethality and deserves further in-depth study.
Journal Article
PARP Inhibitors in Small-Cell Lung Cancer: Rational Combinations to Improve Responses
Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.
Journal Article
The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer
Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.
Journal Article
Apoptotic vesicles are required to repair DNA damage and suppress premature cellular senescence
It is well known that DNA damage can cause apoptosis. However, whether apoptosis and its metabolites contribute to DNA repair is largely unknown. In this study, we found that apoptosis‐deficient Fasmut and Bim−/− mice show significantly elevated DNA damage and premature cellular senescence, along with a significantly reduced number of 16,000 g apoptotic vesicles (apoVs). Intravenous infusion of mesenchymal stromal cell (MSC)‐derived 16,000 g apoVs rescued the DNA damage and premature senescence in Fasmut and Bim−/− mice. Moreover, a sublethal dose of radiation exposure caused more severe DNA damage, reduced survival rate, and loss of body weight in Fasmut mice than in wild‐type mice, which can be recovered by the infusion of MSC‐apoVs. Mechanistically, we showed that apoptosis can assemble multiple nuclear DNA repair enzymes, such as the full‐length PARP1, into 16,000 g apoVs. These DNA repair components are directly transferred by 16,000 g apoVs to recipient cells, leading to the rescue of DNA damage and elimination of senescent cells. Finally, we showed that embryonic stem cell‐derived 16,000 g apoVs have superior DNA repair capacity due to containing a high level of nuclear DNA repair enzymes to rescue lethal dose‐irradiated mice. This study uncovers a previously unknown role of 16,000 g apoVs in safeguarding tissues from DNA damage and demonstrates a strategy for using stem cell‐derived apoVs to ameliorate irradiation‐induced DNA damage.
Journal Article