RESUMEN
Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(iii), ruthenium(ii) and rhenium(i) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.
RESUMEN
G-quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex (Pt1), whose affinity to G4-DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF-G4 (a promoter G4) shows that Pt1 matches 3'-G-tetrad of VEGF-G4 through Cl- -dissociation and loop rearrangement of VEGF-G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate-determining binding step, Cl- -dissociation upon G4-binding, is 2-3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4-binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
Asunto(s)
Antineoplásicos/farmacología , G-Cuádruplex/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Células HeLa , Humanos , Cinética , Estructura Molecular , Compuestos Organoplatinos/químicaRESUMEN
The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6 -methyladenosine (m6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx -PEG NPs elevate RNA m6 A methylation levels to cause the m6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsSx -PEG NPs can regulate the expression of RNA m6 A methyltransferases and demethylases. Finally, DOX@OsSx -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.
Asunto(s)
Nanopartículas , Neoplasias , Línea Celular Tumoral , Doxorrubicina , Humanos , Hipoxia , Metilación , PolietilenglicolesRESUMEN
Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.
Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Mitocondrias/efectos de los fármacos , Nanopartículas/química , Terapia Fototérmica , Profármacos/farmacología , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Cisplatino/química , ADN Mitocondrial/efectos de los fármacos , ADN Mitocondrial/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/metabolismo , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Tamaño de la Partícula , Profármacos/síntesis química , Profármacos/química , Propiedades de SuperficieRESUMEN
Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.
Asunto(s)
Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Inhibidores Enzimáticos/química , Platino (Metal)/química , Profármacos/metabolismo , Timidilato Sintasa/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN , Liberación de Fármacos , Fluorouracilo/metabolismo , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Profármacos/química , Especies Reactivas de Oxígeno/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria-targeted rhenium(I) complex (DFX-Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX-Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX-Re3 affects the events related to apoptosis, RNA polymerases, and T-cell receptor signaling pathways. Finally, it is shown that DFX-Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Asunto(s)
Complejos de Coordinación/química , Hierro/metabolismo , Mitocondrias/metabolismo , Renio/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Deferasirox/química , Evaluación Preclínica de Medicamentos , Epigenómica , Histonas/metabolismo , Humanos , Quelantes del Hierro/química , Metilación/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , ARN Polimerasa II/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both inâ vitro and inâ vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70-90â times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects.
Asunto(s)
Anhidrasa Carbónica IX/antagonistas & inhibidores , Hipoxia de la Célula , Complejos de Coordinación/química , Platino (Metal)/química , Profármacos/química , Animales , Anhidrasa Carbónica IX/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Análisis por Conglomerados , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Larva/efectos de los fármacos , Larva/metabolismo , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Profármacos/metabolismo , Profármacos/farmacología , Profármacos/uso terapéutico , Proteoma/análisis , Proteoma/efectos de los fármacos , Proteómica , Pez Cebra/crecimiento & desarrolloRESUMEN
Cyclometalated iridium(III) complexes represent a promising approach to developing new anticancer metallodrugs. In this work, three phosphorescent cyclometalated iridium(III) complexes Ir1-Ir3 have been explored as mitochondria-targeted anticancer agents. All three complexes display higher antiproliferative activity than cisplatin against the cancer cells screened, and with the IC50 values ranging from 0.23 to 5.6 µM. Colocalization studies showed that these complexes are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy through initiating a series of events related to mitochondrial dysfunction, including depolarization of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS) levels, and induction of apoptosis. Mitochondria-targted cyclometalated iridium complexes induce apoptosis through depolarized mitochondria, elevation of intracellular ROS and activated caspase.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Iridio/farmacología , Mitocondrias/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iridio/química , Mitocondrias/metabolismo , Estructura Molecular , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
G-quadruplex DNA show structural polymorphism, leading to challenges in the use of selective recognition probes for the accurate detection of G-quadruplexes inâ vivo. Herein, we present a tripodal cationic fluorescent probe, NBTE, which showed distinguishable fluorescence lifetime responses between G-quadruplexes and other DNA topologies, and fluorescence quantum yield (Φf ) enhancement upon G-quadruplex binding. We determined two NBTE-G-quadruplex complex structures with high Φf values by NMR spectroscopy. The structures indicated NBTE interacted with G-quadruplexes using three arms through π-π stacking, differing from that with duplex DNA using two arms, which rationalized the higher Φf values and lifetime response of NBTE upon G-quadruplex binding. Based on photon counts of FLIM, we detected the percentage of G-quadruplex DNA in live cells with NBTE and found G-quadruplex DNA content in cancer cells is 4-fold that in normal cells, suggesting the potential applications of this probe in cancer cell detection.
Asunto(s)
ADN/química , G-Cuádruplex , Línea Celular Tumoral , ADN/análisis , Humanos , FotonesRESUMEN
Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Iridio , Neoplasias Experimentales/tratamiento farmacológico , Fotoquimioterapia , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Humanos , Iridio/química , Iridio/farmacología , Metano/análogos & derivados , Metano/síntesis química , Metano/química , Ratones , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
α-Pinene is an important monoterpene that is widely used as a pharmaceutical product, biofuel, and so forth. We first established a cell-free system with modular cocatalysis for the production of pinene from glucose. After optimization of the compositions of the cell-free reaction mixture using the Plackett-Burman experimental design and the path of steepest ascent, the production of pinene increased by 57%. It was found that ammonium acetate, NAD+, and NADPH are the three most important parameters for the production of pinene. Mix-and-match experiments showed that the simultaneous addition of the lysate of Escherichia coli overexpressing native 4-hydroxy-3-methylbut-2-enyl diphosphate reductase, SufBCD Fe-S cluster assembly protein, isopentenyl-diphosphate isomerase, and Pinus taeda pinene synthase improved the production of pinene. Increasing the enzyme concentration of the extract further enhanced the production of pinene to 1256.31 ± 46.12 mg/L with a productivity of 104.7 mg/L h, almost 1.2-fold faster than any system reported thus far. This study demonstrates that a cell-free system is a powerful and robust platform for biomanufacture.
Asunto(s)
Monoterpenos Bicíclicos/química , Escherichia coli/química , Monoterpenos Bicíclicos/metabolismo , Catálisis , Escherichia coli/genética , Escherichia coli/metabolismo , Cinética , NAD/química , NAD/metabolismo , NADP/química , NADP/metabolismoRESUMEN
Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano-platform PDA-Pt-CD@RuFc formed by platinum-decorated and cyclodextrin (CD)-modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene-appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT-PTT) mediated by PDA-Pt-CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non-oxygen-dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near-infrared two-photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor-microenvironment-adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.
RESUMEN
Square-planar cyclometalated platinum(ii) complexes have been found to serve as turn-on phosphorescent probes selectively for biological halogen ions. This is based on the halogen ion induced self-assembly of Pt(ii) compounds in aqueous media, resulting in intermolecular Pt-Pt interaction associated emission.
RESUMEN
We have proposed a facile and cheap cancer therapeutic strategy by in-cell synthesizing theranostic Zn Schiff base complexes with nuclear targeting and DNA damaging capability. The in-cell synthesis can be traced via a green-to-blue fluorescence shift, and the subsequent cytoplasm-to-nucleus translocation realizes cancer-specific therapy both in vitro and in vivo.
Asunto(s)
Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Bases de Schiff/uso terapéutico , Nanomedicina Teranóstica/métodos , Zinc/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Línea Celular Tumoral , Núcleo Celular/metabolismo , Cloruros/química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/toxicidad , Citoplasma/metabolismo , ADN/química , Femenino , Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/uso terapéutico , Colorantes Fluorescentes/toxicidad , Humanos , Hidrólisis , Ratones Endogámicos BALB C , Microscopía Confocal/métodos , Bases de Schiff/síntesis química , Bases de Schiff/metabolismo , Bases de Schiff/toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto , Compuestos de Zinc/químicaRESUMEN
α-Pinene is an important monoterpene, which is widely used as a flavoring agent and in fragrances, pharmaceuticals and biofuels. Although an evolved strain Escherichia coli YZFP, which had higher tolerance to pinene and titer, has been successfully used to produce high levels of pinene, the pinene titer is much lower than that of hemiterpene (isoprene) and sesquiterpenes (farnesene) to date. Moreover, the overall cellular physiological and metabolic changes caused by higher tolerance to pinene and overproduction of pinene remains unclear. To reveal the mechanism of Escherichia coli YZFP with the higher tolerance to pinene and titer, a comparative genomics and transcriptional level analyses combining with CRISPR activation (CRISPRa) and interference (CRISPRi) were carried out. The results show that the tolerance to pinene and the overproduction of pinene in E. coli may be associated with: 1) the mutations of the DXP pathway genes, the rpoA and some membrane protein genes, and their upregulations of transcription levels; and 2) the mutations of some genes and their downregulation of transcriptional levels. These comparative omics analyses provided some genetic modification strategies to further improve pinene production. Overexpression of the mutated cbpA, tabA, pitA, rpoA, sufBCDS, mutS, ispH, oppF, dusB, dnaK, dxs, dxr and flgFGH genes further improved pinene production. This study also demonstrated that combining comparative omics analysis with CRISPRa and CRISPRi is an efficient technology to quickly find a new metabolic engineering strategy.
RESUMEN
Harsh photothermal temperatures, long-term body retention of nanoagents, elevated ROS and inflammation induction all threaten the normal tissues, thus hindering the translation of photothermal therapy (PTT) from bench to clinical practice. To resolve these problems, we have developed a disassembled theranostic nanodrug Qu-FeIIP based on the quercetin coordination. Herein, quercetin is not only the heat shock protein (Hsp 70) inhibitor but also the skeleton of Qu-FeIIP, realizing near-infrared light induced low-temperature PTT (45⯰C) to ablate tumor completely without heat stress to normal tissues. Owing to the ROS scavenging ability of quercetin, Qu-FeIIP effectively reduces intracellular ROS and in vivo inflammatory factors (TNF-α, IL-6, IFN-γ) levels. Simultaneously, quercetin-Fe coordination is weakened when scavenging ROS, which triggers the Qu-FeIIP disassembling, resulting in effective clearance of nanoparticles from main organs 168â¯h post intravenous injection. Additionally, the photoacoustic and magnetic resonance dual-imaging capability of Qu-FeIIP offers excellent spatial resolution and imaging depth not only for precise tumor diagnosis but also for monitoring the nanodrug disassembling in vivo. Thus, Qu-FeIIP intrinsically integrates precise diagnosis, excellent low-temperature PTT efficacy, ROS elimination and anti-inflammatory action, dynamic disassembly and renal clearance ability into a single nanodrug, which is very promising for future clinical cancer treatment.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Compuestos Ferrosos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/terapia , Quercetina/uso terapéutico , Animales , Frío , Crioterapia , Femenino , Humanos , Células MCF-7 , Imagen por Resonancia Magnética , Ratones Endogámicos BALB C , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Técnicas Fotoacústicas , Fototerapia , Especies Reactivas de Oxígeno/metabolismo , Nanomedicina TeranósticaRESUMEN
Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.
RESUMEN
The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Aspirina/uso terapéutico , Complejos de Coordinación/uso terapéutico , Inmunomodulación/efectos de los fármacos , Iridio/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Aspirina/química , Aspirina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Femenino , Humanos , Iridio/química , Iridio/farmacología , Mediciones Luminiscentes/métodos , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Imagen Óptica/métodosRESUMEN
Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Daño del ADN , ADN Mitocondrial/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Iridio/química , Células A549 , Animales , Complejos de Coordinación/química , Cristalografía por Rayos X , ADN Mitocondrial/metabolismo , Células HeLa , Humanos , Ligandos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.