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The development of anti-tumor drugs has notably enhanced the survival rates and quality of life for patients with malignant tumors. However, the side effects of these drugs, especially cardiotoxicity, significantly limit their clinical application. The cardiotoxicity associated with anti-tumor drugs has been a subject of extensive attention and research. Traditional to mitigate these side effects have included reducing drug dosages, shortening treatment duration, modifying administration methods, and opting for drugs with lower toxicity. However, either approach may potentially compromise the anti-tumor efficacy of the medications. Therefore, exploring other effective methods for anti-cardiotoxicity will be the focus of future research. The potential of traditional Chinese medicine (TCM) in managing cardiovascular diseases and cancer treatment has gained widespread recognition. TCM is valued for its minimal side effects, affordability, and accessibility, offering promising avenues in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs. Among its constituents, flavonoids, which are present in many TCMs, are particularly notable. These monomeric compounds with distinct structural components have been shown to possess both cardiovascular protective properties and anti-tumor capabilities. In this discussion, we will delve into the classification of anti-tumor drugs and explore the underlying mechanisms of their associated cardiotoxicity. Additionally, we will examine flavonoids found in TCM and investigate their mechanisms of cardiovascular protection. This will include an analysis of how these natural compounds can mitigate the cardiac side effects of anti-tumor therapies while potentially enhancing overall patient health and treatment outcomes.
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Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Mercadotecnía , Neoplasias/tratamiento farmacológico , Proyectos de Investigación , Estados Unidos , United States Food and Drug AdministrationRESUMEN
BACKGROUND: Nanoscale drug-delivery systems (DDSs) have great promise in tumor diagnosis and treatment. Platelet membrane (PLTM) biomimetic DDSs are expected to enhance retention in vivo and escape uptake by macrophages, as well as minimizing immunogenicity, attributing to the CD47 protein in PLTM sends "don't eat me" signals to macrophages. In addition, P-selectin is overexpressed on the PLTM, which would allow a PLTM-biomimetic DDS to specifically bind to the CD44 receptors upregulated on the surface of cancer cells. RESULTS: In this study, porous nanoparticles loaded with the anti-cancer drug bufalin (Bu) were prepared from a chitosan oligosaccharide (CS)-poly(lactic-co-glycolic acid) (PLGA) copolymer. These were subsequently coated with platelet membrane (PLTM) to form PLTM-CS-pPLGA/Bu NPs. The PLTM-CS-pPLGA/Bu NPs bear a particle size of ~ 192 nm, and present the same surface proteins as the PLTM. Confocal microscopy and flow cytometry results revealed a greater uptake of PLTM-CS-pPLGA/Bu NPs than uncoated CS-pPLGA/Bu NPs, as a result of the targeted binding of P-selectin on the surface of the PLTM to the CD44 receptors of H22 hepatoma cells. In vivo biodistribution studies in H22-tumor carrying mice revealed that the PLTM-CS-pPLGA NPs accumulated in the tumor, because of a combination of active targeting effect and the EPR effect. The PLTM-CS-pPLGA/Bu NPs led to more effective tumor growth inhibition over other bufalin formulations. CONCLUSIONS: Platelet membrane biomimetic nanoparticles played a promising targeted treatment of cancer with low side effect.
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Antineoplásicos/química , Materiales Biomiméticos/química , Bufanólidos/química , Portadores de Fármacos/química , Nanopartículas/química , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Transporte Biológico , Plaquetas/metabolismo , Bufanólidos/efectos adversos , Bufanólidos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Composición de Medicamentos/métodos , Liberación de Fármacos , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos ICR , Oligosacáridos/química , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Distribución TisularRESUMEN
PURPOSE: The retina is continually exposed to free radicals from its rich blood supply, numerous mitochondria, and photons of light which strike its surface. Most pathological processes that take place in the retina, such as inflammation, cell apoptosis, or angiogenesis, can hence involve free radicals directly or indirectly. Since inflammatory and oxidative stress pathways underlie retinal pathology, compounds that address these factors are therefore natural choices for treatment. This review article summarizes and provides commentary on curcumin's therapeutic potential use in ophthalmology with principal focus on retinal dosorders. METHODS: Curcumin (diferuloylmethane) is a compound of the Indian spice turmeric (Curcuma longa) that has been found to be efficacious in preventing and treating a number of inflammatory diseases and neoplastic processes. Curcumin exerts anti-inflammatory, anti-tumor, antioxidant, and VEGF inhibition properties through modulation of numerous biochemical mediators. This makes curcumin particularly effective in retinal disorders. RESULTS: Curcumin has found a role in slowing, and in some cases even reversing, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, proliferative vitreoretinopathy, and retinal cancers. CONCLUSIONS: However, studies on curcumin's efficacy have been limited mostly to animal studies. Moreover, the biomedical potential of curcumin is not easy to use, given its low solubility and oral bioavailability-more attention therefore has been given to nanoparticles and liposomes.
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Curcumina/uso terapéutico , Retina/patología , Enfermedades de la Retina/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Humanos , Enfermedades de la Retina/diagnóstico , Resultado del TratamientoRESUMEN
Aberrant activation of Hedgehog (Hh) signaling is associated with the development of numerous human cancers. Vismodegib is the first Hh inhibitor approved for anti-cancer therapy by targeting Smoothened (SMO), a critical regulator of the Hh pathway. However, acquisition of drug resistance to vismodegib occurs overtime. Apoptosis is a prevalent form of programmed cell death that is executed by caspases. Induction of tumor cell apoptosis represents an attractive therapeutic strategy to eliminate tumor cells. To explore new Hh antagonists with apoptosis-inducing activity, we screened a set of â¼300 potential SMO antagonists with novel scaffold structures. Hh003 was found to induce caspase-dependent apoptosis while vismodegib did not activate apoptotic response in human colon and pancreatic cancer cells. Compared to vismodegib, Hh003 exerted similar inhibitory effects on the Hh pathway. Hh003 could induce caspase8 activation and the silence of caspase8 significantly inhibited Hh003-induced apoptosis. Remarkably, Hh003 showed stronger inhibitory effects on the formation of tumor colonies in vitro and colorectal tumor growth in vivo than vismodegib. These findings suggest that Hh003 exerts enhanced anti-tumor effects by activating caspase8-dependent apoptosis compared to vismodegib. The combined property of Hh inhibition and apoptosis induction of Hh003 presents great potential for the development of novel anti-cancer therapy.
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Anilidas/farmacología , Antineoplásicos/farmacología , Apoptosis/genética , Caspasa 8/metabolismo , Neoplasias del Colon/patología , Proteínas Hedgehog/antagonistas & inhibidores , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Terapia Molecular Dirigida , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: To compare Gehan two-stage design and Simon two-stage design in sample size calculations for phase â ¡ clinical trials of anti-tumor drugs. METHODS: We explained the sample size calculation methods with a single-stage design, Gehan two-stage design, and Simon optimal two-stage and minimax two-stage designs in line with the principle of exact binomial probability. By setting up different parameters in SAS macro program, the advantages and disadvantages of these designs were compared. RESULTS: The minimax two-stage design does not increase the maximum sample size compared with the single-stage design. Compared with the Gehan two-stage design, the Simon two-stage design has the advantage of being able to determine an early termination of trials when no or low anti-tumor activities are evident. CONCLUSION: Simon two-stage design is better than single-stage design and Gehan two-stage design. The minimax design is more popular than the optimal design.
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Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Neoplasias/tratamiento farmacológico , Tamaño de la Muestra , Humanos , Proyectos de InvestigaciónRESUMEN
Chemotherapy is still a prevalent strategy for clinical lung cancer treatment. However, the inevitable emerged drug resistance has become a great hurdle to therapeutic effect. Studies have demonstrated that the primary cause of drug resistance is a decrease in the chemotherapeutic medicine concentration. Several lectins have been confirmed to be effective as chemotherapy adjuvants, enhancing the anti-tumor effects of chemotherapy drugs. Here, we combined phytohemagglutinin (PHA), which has been reported possess anti-tumor effects, with chemotherapy drugs Cisplatin (DDP) and Adriamycin (ADM) on lung cancer cells to detect the sensitivities of PHA as a chemotherapy adjuvant. Our results demonstrated that the PHA significantly enhanced the sensitivity of lung cancer cells to DDP and ADM, and Western blot showed that PHA combined with DDP or ADM enhance cytotoxic effects by inhibiting autophagy and promoting apoptosis. More importantly, we found PHA enhanced the chemotherapeutic drugs cytotoxicity by changing the cell membrane to increase the intracellular chemotherapeutic drugs concentration. Besides, the combination of PHA and ADM increased the ADM concentration in the multidrug-resistant strain A549-R cells and achieved the drug sensitization effect. Our results suggest that PHA combined with chemotherapy can be applied in the treatment of lung cancer cells and lung cancer multidrug-resistant strains, and provide a novel strategy for clinical tumor chemotherapy and a new idea to solve the problem of drug resistance in clinical lung cancer.
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Antineoplásicos , Neoplasias Pulmonares , Phaseolus , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Fitohemaglutininas/farmacología , Fitohemaglutininas/metabolismo , Fitohemaglutininas/uso terapéutico , Phaseolus/metabolismo , Permeabilidad de la Membrana Celular , Resistencia a Antineoplásicos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Apoptosis , Proliferación CelularRESUMEN
The chiral amine (R)-2-(1-aminoethyl)-4-fluorophenol has attracted increasing attentions in recent years in the field of pharmaceuticals because of its important use as a building block in the synthesis of novel anti-tumor drugs targeting tropomyosin receptor kinases. In the present study, a ω-transaminase (ωTA) library consisting of 21 (R)-enantioselective enzymes was constructed and screened for the asymmetric biosynthesis of (R)-2-(1-aminoethyl)-4-fluorophenol from its prochiral ketone. Using (R)-α-methylbenzylamine, D-alanine, or isopropylamine as amino donor, 18 ωTAs were identified with target activity and the enzyme AbTA, which was originally identified from Arthrobacter sp. KNK168, was found to be a potent candidate. The E. coli whole cells expressing AbTA could be used as catalysts. The optimal temperature and pH for the activity were 35-40 °C and pH8.0, respectively. Simple alcohols (such as ethanol, isopropanol, and methanol) and dimethyl sulfoxide were shown to be good cosolvents. High activities were detected when using ethanol and dimethyl sulfoxide at the concentrations of 5-20%. In the scaled-up reaction of 1-liter containing 13 mM ketone substrate, about 50% conversion was achieved in 24 h. 6.4 mM (R)-2-(1-aminoethyl)-4-fluorophenol was generated. After a simple and efficient process of product isolation and purification (with 98.8% recovery), 0.986 g yellowish powder of the product (R)-2-(1-aminoethyl)-4-fluorophenol with high (R)-enantiopurity (up to 100% enantiomeric excess) was obtained. This study established an overall process for the biosynthesis of the high value pharmaceutical chiral amine (R)-2-(1-aminoethyl)-4-fluorophenol by ωTA. Its applicable potential was exemplified by gram-scale production.
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Antineoplásicos , Fenoles , Transaminasas , Dimetilsulfóxido , Escherichia coli , Cetonas , Antineoplásicos/farmacología , Catálisis , EtanolRESUMEN
BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cellsãMacrophages M2ãCD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.
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Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.
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Adjuvant therapy is essential in cancer treatment to enhance primary treatment effectiveness, reduce adverse effects, and prevent recurrence. Small molecule inhibitors as adjuvants in cancer immunotherapy aim to harness their immunomodulatory properties to optimize treatment outcomes. By modulating the tumor microenvironment, enhancing immune cell function, and increasing tumor sensitivity to immunotherapy, small molecule inhibitors have the potential to improve patient responses. This review discusses the evolving use of small molecule inhibitors as adjuvants in cancer treatment, highlighting their role in enhancing the efficacy of immunotherapy and the opportunities for advancing cancer therapies in the future.
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Adyuvantes Inmunológicos , Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Adyuvantes Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Animales , Resistencia a Antineoplásicos , Resultado del TratamientoRESUMEN
Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.
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Background: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound. Methods: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry. Results: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype. Conclusion: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.
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Antineoplásicos , Apoptosis , Proliferación Celular , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ratones , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/síntesis química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Relación Estructura-Actividad , Ratones Endogámicos BALB CRESUMEN
Immune checkpoint inhibitor (ICI)- and phosphatidylinositol-3-kinase inhibitor (PI3Ki)-related diabetes mellitus are common side effects of anti-tumor drug use that present mainly as hyperglycemia. Here, we present two case reports of diabetes mellitus caused by the use of tremelimumab and apalutamide, respectively, in cancer treatment, and a comprehensive, comparative review of the literature on these forms of diabetes. Case 1 presented with diabetic ketoacidosis and was diagnosed with ICI-related diabetes mellitus and treated with insulin. Case 2 was diagnosed with PI3Ki-related diabetes mellitus, and her blood glucose level returned to normal with the use of metformin and dapagliflozin. We systematically searched the PubMed database for articles on ICI- and PI3Ki-related diabetes mellitus and characterized the differences in clinical features and treatment between these two forms of diabetes.
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Antineoplásicos , Diabetes Mellitus , Cetoacidosis Diabética , Hiperglucemia , Femenino , Humanos , Antineoplásicos/efectos adversos , Inhibidores de Puntos de Control Inmunológico , FosfatidilinositolesRESUMEN
DNA origami is a cutting-edge DNA self-assembly technique that neatly folds DNA strands and creates specific structures based on the complementary base pairing principle. These innovative DNA origami nanostructures provide numerous benefits, including lower biotoxicity, increased stability, and superior adaptability, making them an excellent choice for transporting anti-tumor agents. Furthermore, they can considerably reduce side effects and improve therapy success by offering precise, targeted, and multifunctional drug delivery system. This comprehensive review looks into the principles and design strategies of DNA origami, providing valuable insights into this technology's latest research achievements and development trends in the field of anti-tumor drug delivery. Additionally, we review the key function and major benefits of DNA origami in cancer treatment, some of these approaches also involve aspects related to DNA tetrahedra, aiming to provide novel ideas and effective solutions to address drug delivery challenges in cancer therapy.
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BACKGROUND/AIM: Antitumor drug resistance is a major hurdle in treating patients with malignant tumors. Casein kinase 2α (CK2α) expression is highly enhanced in oxaliplatin-resistant CRC cells. We investigated whether CK2α expression is associated with oxaliplatin resistance in CRC cells. MATERIALS AND METHODS: To determine the effect of CK2α on drug resistance in CRC, we assessed the cell viability, adenosine triphosphate-binding cassette (ABC) transporter expression, apoptosis, and sphere formation according to CK2α expression in oxaliplatin-resistant CRC cells. RESULTS: CK2α expression was significantly increased in oxaliplatin-resistant CRC cells compared with that in wild-type CRC cells. In addition, the mRNA expression of ABC transporters, including ABCA12, ABCC2, and ABCE1, was significantly enhanced in oxaliplatin-resistant CRC cells, whereas this effect was blocked by the knockdown of CK2α. Furthermore, a cell viability test showed that oxaliplatin resistance was inhibited by decreasing CK2α expression, resulting in the induction of apoptosis and suppression of sphere formation. CONCLUSION: CK2α regulates cell survival, apoptosis, sphere formation, and drug resistance in oxaliplatin-resistant CRC cells by regulating ABC transporters. Therefore, targeting CK2α in drug-resistant CRC cells may be a novel strategy for treating patients with CRC.
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Quinasa de la Caseína II , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Humanos , Transportadoras de Casetes de Unión a ATP/genética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Oxaliplatino/farmacología , Oxaliplatino/uso terapéuticoRESUMEN
C2H2 zinc finger (C2H2-ZF) proteins are the majority group of human transcription factors and they have many different molecular functions through different combinations of zinc finger domains. Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the main reason for cancer-related deaths worldwide. More and more findings support the abnormal expression of C2H2-ZF protein in the onset and progression of HCC. The C2H2-ZF proteins are involved in various biological functions in HCC, such as EMT, stemness maintenance, metabolic reprogramming, cell proliferation and growth, apoptosis, and genomic integrity. The study of anti-tumor drug resistance also highlights the pivotal roles of C2H2-ZF proteins at the intersection of biological functions (EMT, stemness maintenance, autophagy)and chemoresistance in HCC. The involvement of C2H2-ZF protein found recently in regulating different molecules, signal pathways and pathophysiological activities indicate these proteins as the possible therapeutic targets, and diagnostic or prognostic biomarkers for HCC.
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Tumor cells endure continuous DNA replication stress, which opens the way to cancer development. Despite previous research, the prognostic implications of DNA replication stress on lung adenocarcinoma (LUAD) have yet to be investigated. Here, we aimed to investigate the potential of DNA replication stress-related genes (DNARSs) in predicting the prognosis of individuals with LUAD. Differentially expressed genes (DEGs) originated from the TCGA-LUAD dataset, and we constructed a 10-gene LUAD prognostic model based on DNARSs-related DEGs (DRSDs) using Cox regression analysis. The receiver operating characteristic (ROC) curve demonstrated excellent predictive capability for the LUAD prognostic model, while the Kaplan-Meier survival curve indicated a poorer prognosis in a high-risk (HR) group. Combined with clinical data, the Riskscore was found to be an independent predictor of LUAD prognosis. By incorporating Riskscore and clinical data, we developed a nomogram that demonstrated a capacity to predict overall survival and exhibited clinical utility, which was validated through the calibration curve, ROC curve, and decision curve analysis curve tests, confirming its effectiveness in prognostic evaluation. Immune analysis revealed that individuals belonging to the low-risk (LR) group exhibited a greater abundance of immune cell infiltration and higher levels of immune function. We calculated the immunopheno score and TIDE scores and tested them on the IMvigor210 and GSE78220 cohorts and found that individuals categorized in the LR group exhibited a higher likelihood of deriving therapeutic benefits from immunotherapy intervention. Additionally, we predicted that patients classified in the HR group would demonstrate enhanced sensitivity to Docetaxel using anti-tumor drugs. To summarize, we successfully developed and validated a prognostic model for LUAD by incorporating DNA replication stress as a key factor.
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Autophagy, originally described as a mechanism for intracellular waste disposal and recovery, has been becoming a crucial biological process closely related to many types of human tumors, including breast cancer, osteosarcoma, glioma, etc., suggesting that intervention of autophagy is a promising therapeutic strategy for cancer drug development. Therefore, a high-quality database is crucial for unraveling the complicated relationship between autophagy and human cancers, elucidating the crosstalk between the key autophagic pathways, and autophagic modulators with their remarkable antitumor activities. To achieve this goal, a comprehensive database of autophagic modulators (AMTDB) was developed. AMTDB focuses on 153 cancer types, 1,153 autophagic regulators, 860 targets, and 2,046 mechanisms/signaling pathways. In addition, a variety of classification methods, advanced retrieval, and target prediction functions are provided exclusively to cater to the different demands of users. Collectively, AMTDB is expected to serve as a powerful online resource to provide a new clue for the discovery of more candidate cancer drugs.
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Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.