RESUMEN
The metabolism of massively accumulated chlorogenic acid is crucial for the successful germination of purple coneflower (Echinacea purpurea (L.) Menoch). A serine carboxypeptidase-like (SCPL) acyltransferase (chicoric acid synthase, CAS) utilizes chlorogenic acid to produce chicoric acid during germination. However, it seems that the generation of chicoric acid lags behind the decrease in chlorogenic acid, suggesting an earlier route of chlorogenic acid metabolism. We discovered another chlorogenic acid metabolic product, 3,5-dicaffeoylquinic acid, which is produced before chicoric acid, filling the lag phase. Then, we identified two additional typical clade IA SCPL acyltransferases, named chlorogenic acid condensing enzymes (CCEs), that catalyze the biosynthesis of 3,5-dicaffeoylquinic acid from chlorogenic acid with different kinetic characteristics. Chlorogenic acid inhibits radicle elongation in a dose-dependent manner, explaining the potential biological role of SCPL acyltransferases-mediated continuous chlorogenic acid metabolism during germination. Both CCE1 and CCE2 are highly conserved among Echinacea species, supporting the observed metabolism of chlorogenic acid to 3,5-dicaffeoylquinic acid in two Echinacea species without chicoric acid accumulation. The discovery of SCPL acyltransferase involved in the biosynthesis of 3,5-dicaffeoylquinic acid suggests convergent evolution. Our research clarifies the metabolism strategy of chlorogenic acid in Echinacea species and provides more insight into plant metabolism.
Asunto(s)
Aciltransferasas , Ácido Clorogénico , Echinacea , Germinación , Proteínas de Plantas , Semillas , Germinación/efectos de los fármacos , Ácido Clorogénico/metabolismo , Aciltransferasas/metabolismo , Aciltransferasas/genética , Semillas/efectos de los fármacos , Semillas/crecimiento & desarrollo , Semillas/metabolismo , Echinacea/metabolismo , Echinacea/efectos de los fármacos , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Filogenia , Biocatálisis/efectos de los fármacos , CarboxipeptidasasRESUMEN
High pliability and promiscuity are observed widely exist in plant specialized metabolism, especially the hydroxycinnamic acid metabolism. Here, we identified an addition BAHD acyltransferase (EpHMT) that catalyzes phaselic acid biosynthesis and found that the substrate promiscuities of identified BAHD and SCPL acyltransferases are responsible for the diversity of hydroxycinnamic acid derivatives in purple coneflower.
Asunto(s)
Productos Biológicos , Echinacea , Aciltransferasas/genética , Aciltransferasas/metabolismo , Ácidos Cumáricos , Echinacea/metabolismo , Plantas/metabolismoRESUMEN
The photoisomerization-induced cytotoxicity in photopharmacology provides a unique pathway for phototherapy because it is independent of endogenous oxygen. In this study, we developed a biosafe photoisomerizable zinc(II) complex (Zn1), which releases its trans ligand (trans-L1) after being irradiated with blue light. This causes the complex to undergo photoisomerization and produce the toxic cis product (cis-L1) and generate singlet oxygen (1 O2 ). The resulting series of events caused impressive phototoxicity in hypoxic A431 skin cancer cells, as well as in a tumor model in vivo. Interestingly, Zn1 was able to inhibit tumor microtubule polymerization, while still showing good biocompatibility and biosafety in vivo. This photoisomerizable zinc(II) complex provides a novel strategy for addressing the oxygen-dependent limitation of traditional photodynamic therapy.
Asunto(s)
Fotoquimioterapia , Zinc , Polimerizacion , Fototerapia , Oxígeno , MicrotúbulosRESUMEN
Four photo-catalysts of the general formula [Ir(CO6/ppy)2 (L)]Cl where CO6=coumarin 6 (Ir1-Ir3), ppy=2-phenylpyridine (Ir4), L=4'-(3,5-di-tert-butylphenyl)-2,2' : 6',2''-terpyridine (Ir1), 4'-(3,5-bis(trifluoromethyl)phenyl)-2,2' : 6',2''-terpyridine (Ir2 and Ir4), and 4-([2,2' : 6',2''-terpyridin]-4'-yl)-N,N-dimethylaniline (Ir3) were synthesized and characterized. These photostable photo-catalysts (Ir1-Ir3) showed strong visible light absorption between 400-550â nm. Upon light irradiation (465 and 525â nm), Ir1-Ir3 generated singlet oxygen and induced rapidly photo-catalytic oxidation of cellular coenzymes NAD(P)H. Ir1-Ir3 showed time-dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525â nm), Ir2 provided a much higher photo-index (PI=793) than the clinically used photosensitizer, 5-aminolevulinicacid (5-ALA, PI>30) against HeLa cancer cells. The observed necro-apoptotic anticancer activity of Ir2 was due to the Ir2 triggered photo-induced intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed inâ vivo photo-induced catalytic anticancer activity in mouse models.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Cumarinas , Iridio , Ratones , Oxidación-ReducciónRESUMEN
Sea cucumber-shaped Cu2O nanostructures are constructed on a phosphor-copper mesh by employing a one-step immersion process accomplished in distilled water without introducing any additional reagent. The phosphor-copper mesh with a Cu2O structure thereon exhibits significant hydrophilicity and induces a large superoleophobic force at the oil/water interface. The method used for preparing the Cu2O nanostructures represents an inexpensive, fast, and environmentally friendly approach, along with satisfying the requirements of large-scale preparation. It is found that the pickling degree of the phosphor-copper mesh during surface cleaning plays a major role in the oxidation process of the surface for the growth of Cu2O nanostructures. Nanostructures with different morphologies can be achieved by accurately controlling the surface pickling degree. Interestingly, an underwater superoleophobic "pipe" developed using the as-prepared phosphor-copper mesh can realize gravity (buoyancy)-driven oily liquid transport in an aqueous environment, with no associated contamination by the oil. This study provides a simple method to realize surface-functionalization and demonstrates a new route for achieving liquid transportation without external energy and would help to design smart aquatic devices for diverse liquid transport thereby, enabling oil handling and oil spill cleanup.
RESUMEN
The sulfur-coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS, which contain C,N and S,S (dithione) chelating ligands, were found to inhibit breast cancer tumorigenesis and metastasis by targeting Wnt/ß-catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induces the degradation of LRP6, thereby decreasing the protein levels of DVL2, ß-catenin and activated ß-catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate the stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti-tumor and anti-metastasis effects in mouse xenograft models through the blockage of Wnt/ß-catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Compuestos Organometálicos/química , Azufre/química , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Femenino , Humanos , Iridio/química , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Trasplante Heterólogo , beta Catenina/metabolismoRESUMEN
Photocatalytic anticancer profile of a IrIII photocatalyst (Ir3) with strong light absorption, high turnover frequency, and excellent biocompatibility is reported. Ir3 showed selective photo-cytotoxicity against cisplatin- and sorafenib-resistant cell lines while remaining dormant to normal cell lines in the dark. Ir3 exhibited excellent photo-catalytic oxidation of cellular co-enzyme, the reduced nicotinamide adenine dinucleotide phosphate (NADPH), and amino acids via a single electron transfer mechanism. The photo-induced intracellular redox imbalance and change in mitochondrial membrane potential resulted in necrosis and apoptosis of cancer cells. Importantly, Ir3 exhibited high biocompatibility and photo-catalytic anticancer efficiency as evident from in vivo zebrafish and mouse cancer models. To the best of our knowledge, Ir3 is the first IrIII based photocatalyst with such a high biocompatibility and photocatalytic anticancer therapeutic effect.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Complejos de Coordinación/farmacología , Iridio/farmacología , Fotoquimioterapia , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iridio/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Procesos FotoquímicosRESUMEN
In this Minireview, we highlight recent advances in the design of transition metal complexes for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), and discuss the challenges and opportunities for the translation of such agents into clinical use. New designs for light-activated transition metal complexes offer photoactivatable prodrugs with novel targeted mechanisms of action. Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side-effects. The photophysical and photochemical properties of transition metal complexes can be controlled by the appropriate choice of the metal, its oxidation state, the number and types of ligands, and the coordination geometry.
Asunto(s)
Complejos de Coordinación/química , Metales/química , Fotoquimioterapia/métodos , HumanosRESUMEN
In this article, 3-(3,5-di- tert-butyl-4-hydroxyphenyl) propionic acid (DBHP)-functionalized ZnO (DBHP-ZnO) nanoparticles were synthesized by decomposing the organometallic precursor Zn(DBHP)2 under alkaline conditions. This in situ surface modification method can induce small-sized ZnO nanoparticles (5 nm) and form strong linkage between DBHP and ZnO nanoparticles. DBHP as an organic compound hindered phenol antioxidant that not only improved the dispersion stability of the prepared DBHP-ZnO nanoparticles in the lubrication oil but also scavenged free radicals produced during the oxidation process of oil. Compared with DBHP, the thermal stability of the prepared composite antioxidant was greatly enhanced by introducing inorganic ZnO nanoparticles, which was proved by the results of the thermogravimetric analysis test. A rotary oxygen bomb test, pressurized differential scanning calorimetry, and free-radical-scavenging method all showed that DBHP-ZnO nanoparticles had better antioxidant properties than DBHP under high temperature in the base oil of di- iso-octylsebacate (DIOS). The activation energy of the oxidation process was used to analyze this result by the model-free methods, including the Flynn-Wall-Ozawa method and the Kissinger equation. The calculated results showed that DIOS containing DBHP-ZnO nanoparticles have the lowest reaction constant and the longest half-life period compared to those of individual DBHP and ZnO nanoparticles, which is attributed to the combined action of the organic-inorganic composites. Besides, DBHP-ZnO nanoparticles as the additive are able to improve the antiwear ability of DIOS to some extent. Therefore, the as-prepared DBHP-ZnO nanoparticles with desired dispersibility as well as better thermal stability and antioxidant ability than DBHP in the DIOS base oil could be a potential high-performance nanocomposite additive for a synthetic lubricant base oil like DIOS.
RESUMEN
An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high 1 O2 quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50 ; 0.8-5â µm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
Asunto(s)
Antineoplásicos/farmacología , Núcleo Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Iridio/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Albúmina Sérica Humana/metabolismo , Células A549 , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iridio/química , Modelos Moleculares , Estructura Molecular , Imagen Óptica , Fármacos Fotosensibilizantes/química , Albúmina Sérica Humana/química , Relación Estructura-ActividadRESUMEN
Strongly luminescent iridium(III) complexes, [Ir(C,N)2 (S,S)]+ (1) and [Ir(C,N)2 (O,O)] (2), containing C,N (phenylquinoline), O,O (diketonate), or S,S (dithione) chelating ligands, have been characterized by X-ray crystallography and DFT calculations. Their long phosphorescence lifetimes in living cancer cells give rise to high quantum yields for the generation of 1 O2 , with large 2-photon absorption cross-sections. 2 is nontoxic to cells, but potently cytotoxic to cancer cells upon brief irradiation with low doses of visible light, and potent at sub-micromolar doses towards 3D multicellular tumor spheroids with 2-photon red light. Photoactivation causes oxidative damage to specific histidine residues in the key proteins in aldose reductase and heat-shock protein-70 within living cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of enzymes involved in the glycolytic pathway.
Asunto(s)
Iridio/química , Proteínas de Neoplasias/metabolismo , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Quinolinas/química , Células A549 , Quelantes/química , Cristalografía por Rayos X , Teoría Funcional de la Densidad , Glucólisis , Histidina/química , Humanos , Ligandos , Luminiscencia , Proteínas de Neoplasias/química , Compuestos Organometálicos/química , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Procesos Fotoquímicos , Esferoides Celulares/efectos de los fármacosRESUMEN
BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is a key epigenetic regulator in cancer cell survival, epithelial-mesenchymal transition, and tumorigenesis. Inhibition of EZH2 has become a promising therapeutic option for various human malignancies. Previously, we demonstrated that the EZH2/miR-30d/karyopherin (importin) beta 1 (KPNB1) signaling pathway is critical for malignant peripheral nerve sheath tumor (MPNST) cell survival in vitro and for tumorigenesis in vivo. Here, we sought to determine the antitumor effects of pharmacological inhibition of EZH2 on MPNST in vitro and in vivo. METHODS: We investigated the effects of an EZH2 inhibitor, 3-deazaneplanocin A (DZNep), on MPNST cell cycle, survival and apoptosis in vitro and on MPNST xenograft tumor growth in vivo. RESULTS: We found that DZNep treatment impaired MPNST cell viability and proliferation by inducing apoptosis and cell cycle arrest in vitro. Consistently, DZNep treatment also reduced EZH2 and KPNB1 protein levels and upregulated miR-30d expression in MPNST cells. Intraperitoneal administration of DZNep significantly suppressed MPNST tumor initiation and growth rates in a MPNST xenograft mouse model. Immunoblot and immunohistochemical analyses showed that DZNep downregulated EZH2/KPNB1 signaling in vivo, thereby inhibiting MPNST tumor cell proliferation, and induced cell death. We also found that EZH2 inhibited expression of another miR-30 family member, miR-30a, in MPNST cells. Similar to miR-30d, miR-30a inhibited KPNB1 by targeting the KPNB1 3' untranslated region in MPNST cells. Our data also showed that EZH2 suppressed miR-200b expression and induced epithelial-mesenchymal transition in MPNST cells. CONCLUSION: These findings demonstrated that DZNep, an inhibitor of S-adenosyl-methionine-dependent methyltransferase, suppressed EZH2/miR-30a,d/KPNB1 signaling and blocked MPNST tumor cell growth and survival in vitro and in vivo. More importantly, our study indicated that pharmacological interference of EZH2 is a potential therapeutic approach for MPNST.
Asunto(s)
MicroARNs/genética , Neoplasias de la Vaina del Nervio/genética , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Complejo Represivo Polycomb 2/genética , Transducción de Señal/efectos de los fármacos , beta Carioferinas/genética , Regiones no Traducidas 3'/efectos de los fármacos , Regiones no Traducidas 3'/genética , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Proteína Potenciadora del Homólogo Zeste 2 , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Ratones , Ratones SCID , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Transducción de Señal/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
The aim of this study was to illustrate the dramatically different anticancer activities between coordinatively saturated polypyridyl (1 a-4 a) and cyclometalated (1 b-4 b) ruthenium(II) complexes. The cyclometalated complexes 1 b-4 b function as DNA transcription inhibitors, exhibiting switch-on cytotoxicity against a 2D cancer cell monolayer, whereas the polypyridyl complexes 1 a-4 a are relatively inactive. Moreover, complexes 1 b-4 b exhibit excellent cytotoxicity against 3D multicellular tumor spheroids (MCTSs), which serve as an intermediate model between in vitro 2D cell monolayers and in vivo 3D solid tumors. The hydrophobicity, efficient cell uptake, and nucleus targeting ability, as well as the high DNA binding affinity of complexes 1 b-4 b, likely contribute to their enhanced anticancer activity. We surmise that cyclometalation could be a universal approach to significantly enhance the anticancer activity of substituted polypyridyl Ru(II) complexes. We also suggest that 3D MCTSs may be a more practical platform for anticancer drug screening than 2D cancer monolayer approaches.
Asunto(s)
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , ADN/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HeLa , Humanos , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Esferoides Celulares , Activación Transcripcional/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Malignant peripheral nerve sheath tumours (MPNSTs), which develop sporadically or from neurofibromatosis, recur frequently with high metastatic potential and poor outcome. The polycomb group protein enhancer of zeste homologue 2 (EZH2) is an important regulator for various human malignancies. However, the function of EZH2 in MPNSTs is unknown. Here we report that the EZH2-miR-30d-KPNB1 signalling pathway is critical for MPNST tumour cell survival in vitro and tumourigenicity in vivo. Up-regulated EZH2 in MPNST inhibits miR-30d transcription via promoter binding activity, leading to enhanced expression of the nuclear transport receptor KPNB1 that is inhibited by miR-30d targeting of KPNB1 3' UTR region. Furthermore, inhibition of EZH2 or KPNB1, or miR-30d over-expression, induces MPNST cell apoptosis in vitro and suppresses tumourigenesis in vivo. More importantly, forced over-expression of KPNB1 rescues MPNST cell apoptosis induced by EZH2 knockdown. Immunohistochemical analyses show that EZH2 and KPNB1 over-expression is observed in human MPNST specimens and is negatively associated with miR-30d expression. Our findings identify a novel signalling pathway involved in MPNST tumourigenesis, and also suggest that EZH2-miR-30d-KPNB1 signalling represents multiple potential therapeutic targetable nodes for MPNST.
Asunto(s)
Transformación Celular Neoplásica , MicroARNs/metabolismo , Neurilemoma/metabolismo , Complejo Represivo Polycomb 2/metabolismo , beta Carioferinas/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , Supervivencia Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Inmunoprecipitación de Cromatina , Proteína Potenciadora del Homólogo Zeste 2 , Regulación Neoplásica de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Ratones SCID , MicroARNs/genética , Neurilemoma/genética , Neurilemoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Complejo Represivo Polycomb 2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Análisis de Matrices Tisulares , Regulación hacia Arriba , beta Carioferinas/genéticaRESUMEN
Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two-photon cross-sections around 800 nm, which limits their potential use in TP-PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two-photon photodynamic therapy.
Asunto(s)
Complejos de Coordinación/farmacología , Lisosomas/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Piridinas/química , Rutenio/química , Muerte Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Células HeLa , Humanos , Lisosomas/química , Fotones , Fármacos Fotosensibilizantes/síntesis química , Polímeros/química , Polímeros/farmacología , Piridinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Rutenio/farmacologíaRESUMEN
A series of novel chiral ruthenium(II) polypyridyl complexes (Δ-Ru1, Λ-Ru1, Δ-Ru2, Λ-Ru2, Δ-Ru3, Λ-Ru3) were synthesized and evaluated to determine their antiproliferative activities. Colocalization, inductively coupled plasma mass spectrometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay studies showed that these ruthenium(II) complexes accumulated preferentially in the mitochondria and exhibited cytotoxicity against various cancer cells in vitro. The complex Δ-Ru1 is of particular interest because it was found to have half-maximal inhibitory concentrations comparable to those of cisplatin and better activity than cisplatin against a cisplatin-resistant cell line, A549-CP/R. Δ-Ru1 induced alterations in the mitochondrial membrane potential and triggered intrinsic mitochondria-mediated apoptosis in HeLa cells, which involved the regulation of Bcl-2 family members and the activation of caspases. Taken together, these data suggest that Δ-Ru1 may be a novel mitochondria-targeting anticancer agent.
Asunto(s)
Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Mitocondrias/efectos de los fármacos , Piridinas/administración & dosificación , Rutenio/administración & dosificación , Antineoplásicos/química , Apoptosis/fisiología , Línea Celular Tumoral , Células HeLa , Células Hep G2 , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Mitocondrias/patología , Piridinas/química , Rutenio/químicaRESUMEN
Due to cell mutation and self-adaptation, the application of clinical drugs with early epidermal growth factor receptor (EGFR)-targeted inhibitors is severely limited. To overcome this limitation, herein, the synthesis and in-depth biological evaluation of an erlotinib-platinum(II) complex as an EGFR-targeted anticancer agent is reported. The metal complex is able to self-assemble inside an aqueous solution and readily form nanostructures with strong photophysical properties. While being poorly toxic toward healthy cells and upon treatment in the dark, the compound was able to induce a cytotoxic effect in the very low micromolar range upon irradiation against EGFR overexpressing (drug resistant) human lung cancer cells as well as multicellular tumor spheroids. Mechanistic insights revealed that the compound was able to selectively degrade the EGFR using the lysosomal degradation pathway upon generation of singlet oxygen at the EGFR. We are confident that this work will open new avenues for the treatment of EGFR-overexpressing tumors.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Fotoquimioterapia , Humanos , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Platino (Metal)/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/patología , Receptores ErbB/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resistencia a Antineoplásicos , Línea Celular TumoralRESUMEN
The hypoxic microenvironment of solid tumors severely lowers the efficacy of oxygen-dependent photodynamic therapy (PDT). The development of hypoxia-tolerant photosensitizers for PDT is an urgent requirement. In this study, a novel rhenium complex (Re-TTPY) to develop a "closed-loop" therapy based on PDT-induced ferroptosis and immune therapy is reported. Due to its electron donor-acceptor (D-A) structure, Re-TTPY undergoes energy transfer and electron transfer processes under 550 nm light irradiation and displays hypoxia-tolerant type I/II combined PDT capability, which can generate 1O2, O2 -, and ·OH simultaneously. Further, the reactive oxygen species (ROSs) leads to the depletion of 1,4-dihydronicotinamide adenine dinucleotide (NADH), glutathione peroxidase 4 (GPX4), and glutathione (GSH). As a result, ferroptosis occurs in cells, simultaneously triggers immunogenic cell death (ICD), and promotes the maturation of dendritic cells (DCs) and infiltration of T cells. The release of interferon-γ (IFN-γ) by CD8+ T cells downregulates the expression of GPX4, further enhancing the occurrence of ferroptosis, and thereby, forming a mutually reinforcing "closed-loop" therapeutic approach.
Asunto(s)
Ferroptosis , Inmunoterapia , Fotoquimioterapia , Fármacos Fotosensibilizantes , Renio , Ferroptosis/efectos de los fármacos , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Animales , Ratones , Humanos , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Renio/química , Renio/farmacología , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Femenino , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Sonodynamic therapy (SDT), as a novel non-invasive cancer treatment modality derived from photodynamic therapy (PDT), has drawn much attention due to its unique advantages for the treatment of deep tumors. Zinc-based complexes have shown great clinical prospect in PDT due to their excellent photodynamic activity and biosafety. However, their application in SDT has lagged seriously behind. Exploring efficient zinc-based complexes as sono-sensitizers remains an appealing but significantly challenging task. Herein, we develop a hydrazone ligand-based zinc complex (ZnAMTC) for SDT of tumors in vitro and in vivo. ZnAMTC was facilely synthesized via a two-step reaction from low-cost raw materials without tedious purification. It shows negligible dark toxicity and can produce singlet oxygen (1O2) under ultrasound (US) irradiation, exhibiting high sono-cytotoxicity to various cancer cells. Mechanism studies show that ZnAMTC can effectively reduce the levels of glutathione (GSH) and glutathione peroxidase 4 (GPX4) under US irradiation and later cause ferroptosis of cancer cells. In vivo studies further demonstrate that ZnAMTC exhibits efficient tumor growth inhibition under US irradiation and has good biosafety. This work provides useful insights into the design of first-row transition metal complexes for SDT application.
RESUMEN
The design of the dinuclear Ru(II) complex (Ru2) with strong near-infrared (NIR) absorption properties has been reported for efficient anticancer phototherapy. Under 700 nm LED light excitation, Ru2 exhibited remarkable synergistic type I/II photosensitization ability and photocatalytic activity toward intracellular biomolecules. Ru2 showed impressive 700 nm light-triggered anticancer activity under normoxia and hypoxia compared with the clinically used photosensitizer Chlorin e6. The mechanistic studies showed that Ru2 induced intracellular redox imbalance and perturbed the energy metabolism and biosynthesis in A549 cancer cells. Overall, this work provides a new strategy for developing efficient metal-based complexes for anticancer phototherapy under NIR light.