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Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin-uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga-CT@P nanocomposites constructed with gallium, copper-doped tetrakis (4-carboxyphenyl) porphyrin (TCPP) metal-organic framework, and polyamine-amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium-incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real-time fluorescent iron-sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga-CT@P nanocomposites induced long-term iron starvation, which affected iron-sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.
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Infecciones Bacterianas , Galio , Porfirinas , Humanos , Hierro/metabolismo , Hemina/metabolismo , Bacterias/metabolismo , Antibacterianos/metabolismo , Biopelículas , Galio/farmacología , Porfirinas/farmacología , Porfirinas/metabolismo , Infecciones Bacterianas/tratamiento farmacológico , Homeostasis , Iones/metabolismo , Polímeros/metabolismoRESUMEN
Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.
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Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.
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Membranas Mitocondriales , Neoplasias , Humanos , Membranas Mitocondriales/metabolismo , Protones , Neoplasias/patología , Células Madre Neoplásicas/metabolismoRESUMEN
The development of superior photoelectrochemical (PEC) sensors for biosensing has become a major objective of PEC research. However, conventional PEC-active materials are typically constrained by a weak photocurrent response owing to their limited surface-active sites and high electron-hole recombination rate. Here, a boron and graphene quantum dots codoped g-C3N4 (named GBCN) as PEC sensor for highly sensitive dopamine (DA) detection was fabricated. GBCN exhibited the greatest photocurrent response and PEC activity compared to free g-C3N4 and g-C3N4 doped with boron. The proposed PEC sensor for DA determination exhibited a broad linear range (0.001-800 µM) and a low detection limit (0.96 nM). In particular, a sensitivity up to 10.3771 µA/µM/cm2 was seen in the case of GBCN. The high PEC activity can be attributed to the following factors: (1) the boron and graphene quantum dots co-doping significantly increased the specific surface area of g-C3N4, providing more adsorption sites for DA; (2) the dopants extended the absorption intensity of g-C3N4, red-shifting the absorption from 470 to 540 nm; and (3) the synergism of boron and graphene quantum dots efficiently boosted the photogenerated electrons migration from the conduction band of g-C3N4 to graphene quantum dots, facilitating charge separation. In addition, GBCN also exhibited good anti-interference ability and stability. This research may shed light on the creation of a highly sensitive and selective PEC platform for detecting biomolecules.
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Técnicas Biosensibles , Grafito , Puntos Cuánticos , Grafito/química , Puntos Cuánticos/química , Dopamina , Boro , Técnicas Electroquímicas , Límite de DetecciónRESUMEN
Mechanical stimulation utilizing deep tissue-penetrating and focusable energy sources, such as ultrasound and magnetic fields, is regarded as an emerging patient-friendly and effective therapeutic strategy to overcome the limitations of conventional cancer therapies based on fundamental external stimuli such as light, heat, electricity, radiation, or microwaves. Recent efforts have suggested that mechanical stimuli-driven cancer therapy (henceforth referred to as "mechanical cancer therapy") could provide a direct therapeutic effect and intelligent control to augment other anti-cancer systems as a synergistic combinational cancer treatment. This review article highlights the latest advances in mechanical cancer therapy to present a novel perspective on the fundamental principles of ultrasound- and magnetic field-mediated mechanical forces, including compression, tension, shear force, and torque, that can be generated in a cellular microenvironment using mechanical stimuli-activated functional materials. Additionally, this article will shed light on mechanical cancer therapy and inspire future research to pursue the development of ultrasound- and magnetic-field-activated materials and their applications in this field.
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Neoplasias , Humanos , Neoplasias/terapia , Fenómenos Mecánicos , Campos Magnéticos , Microambiente TumoralRESUMEN
Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances.
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Antineoplásicos , COVID-19 , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Muerte Celular Inmunogénica , Inmunoterapia , Neoplasias/terapia , Pandemias , SARS-CoV-2RESUMEN
Non-invasive dynamic tracking of lysosomes and their interactions with other organelles is important for the study of lysosomal function and related diseases. However, many fluorescent dyes developed so far to target lysosomes cannot be used to monitor these processes due to the high concentrations required for imaging, long cell penetration times, and non-ideal photostability. In this regard, we synthesized three lysosomal targeting probes with large Stokes shifts, good stability, and high brightness. The Q-P-ARh dye, developed by us for the first time, can stain lysosomes at ultra-low concentrations (1.0â nM) without affecting the physiological functions of the lysosomes. More importantly, its excellent anti-interference ability and ultrafast lysosomal staining ability (within 1.0â min) clearly monitored the entire dynamic process of lipophagy. Ultimately, this method can greatly contribute to the study of autophagy pathways. This novel fluorescence platform shows great promise for the development of biological probes for application in pathological environments.
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Autofagia , Fluorescencia , Colorantes Fluorescentes/química , Imagen Óptica , Colorantes Fluorescentes/síntesis química , Células Hep G2 , Humanos , Lisosomas/químicaRESUMEN
Aldehyde dehydrogenase (ALDH), a cancer stem cell biomarker, is related to drug resistance. Co-treatment of anti-cancer drug (CPT) and ALDH inhibitor (DEAB) can overcome the drug resistance of cancer stem cells (CSCs) and finally cure cancers without relapse. We herein introduce a prodrug (DE-CPT) - consisting of 1,3-oxathiolane as an ROS responsive scaffold, and an aldehyde protecting group of DEAB - to deliver the CPT and DEAB upon reaction with ROS. From tests of the sphere-forming ability and CSC marker subpopulation, we found that DE-CPT efficiently decreases the CSCs population and kills the cancer cells.
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Aldehído Deshidrogenasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Tiofenos/farmacología , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Células Madre Neoplásicas/metabolismo , Profármacos/química , Profármacos/metabolismo , Tiofenos/química , Tiofenos/metabolismoRESUMEN
Precise detection of cellular senescence may allow its role in biological systems to be evaluated more effectively, while supporting studies of therapeutic candidates designed to evade its detrimental effect on physical function. We report here studies of α-l-fucosidase (α-fuc) as a biomarker for cellular senescence and the development of an α-fuc-responsive aggregation induced emission (AIE) probe, termed QM-NHαfuc designed to complement more conventional probes based on ß-galactosidase (ß-gal). Using QM-NHαfuc, the onset of replicative-, reactive oxygen species (ROS)-, ultraviolet A (UVA)-, and drug-induced senescence could be probed effectively. QM-NHαfuc also proved capable of identifying senescent cells lacking ß-gal expression. The non-invasive real-time senescence tracking provided by QM-NHαfuc was validated in an in vivo senescence model. The results presented in this study lead us to suggest that the QM-NHαfuc could emerge as a useful tool for investigating senescence processes in biological systems.
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Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.
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Antineoplásicos/uso terapéutico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Carcinogénesis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Acetazolamida/análogos & derivados , Acetazolamida/uso terapéutico , Animales , Antineoplásicos/síntesis química , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Curcumina/análogos & derivados , Curcumina/síntesis química , Curcumina/uso terapéutico , Diarilheptanoides/síntesis química , Diarilheptanoides/uso terapéutico , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/uso terapéutico , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/diagnóstico por imagen , Esferoides Celulares/efectos de los fármacos , Tiofenos/síntesis química , Tiofenos/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The insistent demand for space-controllable delivery, which reduces the side effects of non-steroidal anti-inflammatory drugs (NSAIDs), has led to the development of a new theranostics-based approach for anti-inflammatory therapy. The current anti-inflammatory treatments can be improved by designing a drug delivery system responsive to the inflammatory site biomarker, hydrogen polysulfide (H2Sn). Here, we report a novel theranostic agent 1 (TA1), consisting of three parts: H2Sn-mediated triggering part, a two-photon fluorophore bearing mitochondria targeting unit (Rhodol-TPP), and anti-inflammatory COX inhibitor (indomethacin). In vitro experiments showed that TA1 selectively reacts with H2Sn to concomitantly release both Rhodol-TPP and indomethacin. Confocal-microscopy imaging of inflammation-induced live cells suggested that TA1 is localized in the mitochondria where the H2Sn is overexpressed. The TA1 reacted with H2Sn in the endogenous and exogenous H2Sn environments and in lipopolysaccharide treated inflammatory cells. Moreover, TA1 suppressed COX-2 level in the inflammatory-induced cells and prostaglandin E2 (PGE2) level in blood serum from inflammation-induced mouse models. In vivo experiments with inflammation-induced mouse models suggested that TA1 exhibits inflammation-site-elective drug release followed by significant therapeutic effects, showing its function as a theranostic agent, capable of both anti-inflammatory therapy and precise diagnosis. Theranostic behavior of TA1 is highly applicable in vivo model therapeutics for the inflammatory disease.
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Abnormal microenvironments (viscosity, polarity, pH, etc.) have been verified to be closely associated with numerous pathophysiological processes such as inflammation, neurodegenerative diseases, and cancer. As a result, deep insights into these pathophysiological microenvironments are particularly beneficial for clinical diagnosis and treatment. However, the monitoring of pathophysiological microenvironments is unattainable by the traditional clinical diagnostic techniques such as magnetic resonance imaging, computed tomography, and positron emission tomography. Recently, fluorescence imaging has shown tremendous advantages and potential in the tracing of pathophysiological microenvironment variations. In this context, a general discussion is provided on the state-of-the-art progress of fluorescent probes for visualizing pathophysiological microenvironments (viscosity, pH, and polarity), since 2016, as well as the future perspectives in this challenging field.
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Microambiente Celular , Colorantes Fluorescentes/análisis , Imagen Óptica , Animales , FluorescenciaRESUMEN
Peroxynitrite (ONOO-), a powerful biological oxidant, is produced in the mitochondria and reacts with many biomolecular targets under various pathological conditions, leading to a range of disease states. In this work, we developed a nanoliposome-encapsulated ratiometrically fluorescent probe (NRF) based on a hemicyanine structure Cy-O obtained by facile synthesis. Upon reaction with ONOO-, the oxidation and hydrolysis of a π-conjugation system within the nanoliposome triggers a ratiometrically fluorescent response and a large-scale emission shift (238 nm), which provides a specific and sensitive means for the ONOO- detection. Moreover, we have performed DFT calculation at the 6-31+G(d,p) level using a suite of Gaussian 09 programs to obtain insights into the chemical structure optical properties of Cy-O. In addition, the practical applications of the nanoprobe to image exogenous and endogenous ONOO- were achieved further in live cells and animals triumphantly.
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Materiales Biocompatibles/química , Colorantes Fluorescentes/química , Nanopartículas/química , Ácido Peroxinitroso/análisis , Animales , Materiales Biocompatibles/síntesis química , Teoría Funcional de la Densidad , Colorantes Fluorescentes/síntesis química , Células Hep G2 , Humanos , Liposomas/química , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Ensayo de Materiales , Ratones , Estructura Molecular , Imagen Óptica , Tamaño de la PartículaRESUMEN
Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both inâ vitro and inâ vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.
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Compuestos de Boro/química , Ácido Etacrínico/química , Fármacos Fotosensibilizantes/química , Especies Reactivas de Oxígeno/metabolismo , Animales , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Gutatión-S-Transferasa pi/antagonistas & inhibidores , Gutatión-S-Transferasa pi/metabolismo , Halogenación , Humanos , Luz , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Trasplante HeterólogoRESUMEN
Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugating ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX), is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial relocalization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially-mediated oxidative damage.
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Neurodegenerative diseases are debilitating disorders that feature progressive and selective loss of function or structure of anatomically or physiologically associated neuronal systems. Both chronic and acute neurodegenerative diseases are associated with high morbidity and mortality along with the death of neurons in different areas of the brain; moreover, there are few or no effective curative therapy options for treating these disorders. There is an urgent need to diagnose neurodegenerative disease as early as possible, and to distinguish between different disorders with overlapping symptoms that will help to decide the best clinical treatment. Recently, in neurodegenerative disease research, fluorescent-probe-mediated biomarker visualization techniques have been gaining increasing attention for the early diagnosis of neurodegenerative diseases. A survey of fluorescent probes for sensing and imaging biomarkers of neurodegenerative diseases is provided. These imaging probes are categorized based on the different potential biomarkers of various neurodegenerative diseases, and their advantages and disadvantages are discussed. Guides to develop new sensing strategies, recognition mechanisms, as well as the ideal features to further improve neurodegenerative disease fluorescence imaging are also explored.
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Colorantes Fluorescentes/metabolismo , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/metabolismo , HumanosRESUMEN
Cancer stem cells (CSCs), also called tumor-initiating cells (TICs), have been studied intensively due to their rapid proliferation, migration, and role in the recurrence of cancer. In general, CSC marker-positive cells [CD133, CD44, CD166, aldehyde dehydrogenase (ALDH), and epithelial cell adhesion molecule (EpCAM)] exhibit a 100-fold increased capacity to initiate cancer. Within a heterogeneous tumor mass, only approximately 0.05-3% of cells are suspected to be CSCs and able to proliferate under hypoxia. Interestingly, CSCs, cancer cells, and normal stem cells share many cytochemical properties, such as inhibition of the redox system for reactive oxygen species (ROS) production and high expression of drug resistance transporters. However, compared to normal stem cells, CSCs develop unique metabolic flexibility, which involves switching between oxidative phosphorylation (OXPHOS) and glycolysis as their main source of energy. Due to the similarities between CSCs and other cancer cells and normal stem cells, limited chemotherapeutic and bio-imaging reagents specific for CSCs have been developed. In this short review, we address the current knowledge regarding CSCs with a focus on designing chemotherapeutic and bio-imaging reagents that target CSCs.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/análisis , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
Heteroatom-containing spiropolymers were constructed in a facile manner by a catalyst-free multicomponent spiropolymerization route. P1a2b as the most potent of these spiropolymers, demonstrates cluster-triggered emission resulting from strong interactions with the MDM2 protein. By preventing the anti-apoptotic p53/MDM2 interaction, P1a2b triggers apoptosis in cancerous cells, while demonstrating a good biocompatibility and non-toxicity in non-cancerous cells. The combined results from solution and cell-based cluster-triggered emission studies, docking, protein expression experiments and cytotoxicity data strongly support the MDM2-binding hypothesis and indicate a potential application as a fluorescent cancer marker as well as therapeutic for this spiropolymer.
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Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Línea Celular Tumoral , Humanos , Medicina de Precisión , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Mitochondrial enzyme monoamine oxidase (MAO-A) is known to be overexpressed in prostate cancer (PCa) cells. Herein, we have developed a two-photon probe (PCP-1) for selectively targeting and imaging the MAO-A in PCa. Supported by enzymatic docking and in vitro experiments, PCP-1 showed efficiency to visualize MAO-A overexpressing cells and inhibit their growth and metastasis potential.
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Antineoplásicos/química , Colorantes Fluorescentes/química , Inhibidores de la Monoaminooxidasa/química , Monoaminooxidasa/análisis , Neoplasias de la Próstata/diagnóstico por imagen , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/farmacología , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Imagen Óptica , Fotones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismoRESUMEN
Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN-38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.