RESUMEN
Radionuclides internal radiotherapy (RIT) is a clinically powerful method for cancer treatment, but still poses unsatisfactory therapeutic outcomes due to the hypoxic characteristic of tumor microenvironment (TME). Catalase (CAT) or CAT-like nanomaterials can be used to enzymatically decompose TME endogenous H2O2 to boost TME oxygenation and thus alleviate the hypoxic level within tumors, but their effectiveness is still hindered by the short-lasting of hypoxia relief owing to their poor stability or degradability, thereby failing to match the long therapeutic duration of RIT. Herein, we proposed an innovative strategy of using facet-dependent CAT-like Pd-based two-dimensional (2D) nanoplatforms to continuously enhance RIT. Specifically, rationally designed 2D Pd@Au nanosheets (NSs) enable consistent enzymatic conversion of endogenous H2O2 into O2 to overcome hypoxia-induced RIT resistance. Furthermore, partially coated Au layer afford NIR-II responsiveness and moderate photothermal treatment that augmenting their enzymatic functionality. This approach with dual-effect paves the way for reshaping TME and consequently facilitating the brachytherapy ablation of cancer. Our work offers a significant advancement in the integration of catalytic nanomedicine and nuclear medicine, with the overarching goal of amplifying the clinical benefits of RIT-treated patients.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Peróxido de Hidrógeno , Microambiente Tumoral , Hipoxia/tratamiento farmacológico , Catálisis , Nanomedicina , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapiaRESUMEN
Clonorosins A (1) and B (2), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids (3-9), were isolated from the soil-derived fungus Clonostachys rosea YRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i-3iv were synthesized and analyzed. 1 was active against Fusarium oxysporum with an MIC value of 50 µg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50 values of 0.12-0.60 µM.
Asunto(s)
Antibacterianos/farmacología , Hypocreales/química , Alcaloides Indólicos/farmacología , Antibacterianos/aislamiento & purificación , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Células HeLa , Células Hep G2 , Humanos , Alcaloides Indólicos/aislamiento & purificación , Estructura Molecular , Microbiología del SueloRESUMEN
Isolation and identification of natural products from plants is an essential approach for discovering drug candidates. Herein we report the characterization of three sesquiterpene lactones from a new genus Shangwua, e.g. onopordopicrin (ONP), C2, and C3, and evaluation of their pharmacological functions in interfering cellular redox signaling. Compared to C2 and C3, ONP shows the most potency in killing cancer cells. Further experiments demonstrate that ONP robustly inhibits thioredoxin reductase (TrxR), which leads to perturbation of cellular redox homeostasis with the favor of oxidative stress. Knockdown of the TrxR sensitizes cells to the ONP treatment while overexpression of the enzyme reduces the potency of ONP, underpinning the correlation of TrxR inhibition to the cytotoxicity of ONP. The discovery of ONP expands the library of the natural TrxR inhibitors, and the disclosure of the action mechanism of ONP provides a foundation for the further development of ONP as an anticancer agent.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Asteraceae/química , Inhibidores Enzimáticos/farmacología , Lactonas/farmacología , Sesquiterpenos/farmacología , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Lactonas/química , Lactonas/aislamiento & purificación , Simulación del Acoplamiento Molecular , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-Actividad , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Células Tumorales CultivadasRESUMEN
Overexpression of the selenoprotein thioredoxin reductase (TrxR) has been documented in malignant tissues and is of pathological significance for many types of tumors. The antibiotic puromycin (Puro) is a protein synthesis inhibitor causing premature polypeptide chain termination during translation. The well-defined action mechanism of Puro makes it a useful tool in biomedical studies. However, the nonselective cytotoxicity of Puro limits its therapeutic applications. We report herein the construction and evaluation of two Puro prodrugs, that is, S1-Puro with a five-membered cyclic disulfide trigger and S2-Puro with a linear disulfide trigger. S1-Puro is selectively activated by TrxR and shows the TrxR-dependent cytotoxicity to cancer cells, while S2-Puro is readily activated by thiols. Furthermore, S1-Puro displays higher stability in plasma than S2-Puro. We expect that this prodrug strategy may promote the further development of Puro as a therapeutic agent.
Asunto(s)
Profármacos , Reductasa de Tiorredoxina-Disulfuro , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Profármacos/farmacología , Puromicina/farmacologíaRESUMEN
INTRODUCTION: The thioredoxin system is increasingly recognized as an important executor for maintaining cell redox homeostasis and regulating multiple cell signaling pathways. Targeting this system for cancer treatment has therefore attracted much attention. AREAS COVERED: The authors focus on providing coverage and emphasizing the strategy of targeting the thioredoxin system to develop anticancer therapeutics in the past five years, especially from the perspective of discovering novel protein functions or new downstream regulatory pathways, and designing new therapeutic reagents. The authors also provide the readers with their expert perspectives for future development. EXPERT OPINION: The limited pharmacophore of inhibitors and the slow progress of clinical research partially restrict the development of anticancer drugs targeting the thioredoxin system, necessitating thus novel strategies to accelerate the system for treating cancer. Nevertheless, the synergistic targeting of thioredoxin system for cancer therapy is a promising strategy, particularly with regards to chemotherapy resistance and/or sensitization immunotherapy.
Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Tiorredoxinas/metabolismo , Tiorredoxinas/uso terapéuticoRESUMEN
ß-Lapachone as a natural novel anticancer candidate is under clinical trials. Previous studies suggested that ß-lapachone works by redox activation to ablate cancer cells. However, it is still unclear whether thioredoxin reductase (TrxR), one of the key redox catalytic enzymes in cells, plays a role in the pharmacological effects of ß-lapachone. Herein, we present that ß-lapachone kills human promyelocytic leukemia HL-60 cells with preference over other cancer cells and normal cells. The follow-up studies demonstrate that ß-lapachone induces the HL-60 cell apoptosis through inhibition of TrxR and further elevation of oxidative stress. Overexpression of the TrxR alleviates the efficiency of ß-lapachone while knockdown of the enzyme increases the ß-lapachone cytotoxicity, scientifically underpinning the correlation of the observed biological behaviors of ß-lapachone to TrxR inhibition. The disclosure of the novel action mechanism of ß-lapachone sheds light on understanding its capacity in interfering with cellular redox signaling and supports ß-lapachone as an anticancer drug candidate.
Asunto(s)
Apoptosis , Reductasa de Tiorredoxina-Disulfuro , Células HL-60 , Humanos , Naftoquinonas , Oxidación-Reducción , Especies Reactivas de Oxígeno/farmacología , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis, while dysregulation of redox homeostasis is a hallmark for cancer cells. Thus, there is considerable potential to inhibit the aberrantly upregulated TrxR in cancer cells to discover selective cancer therapeutic agents. Nevertheless, the structural types of TrxR inhibitors presented currently are still relatively limited. We herein report that PACMA 31, previously reported to inhibit protein disulfide isomerase (PDI), is a potent TrxR inhibitor. PACMA 31 possesses a pharmacophore scaffold that is structurally different from the announced TrxR inhibitors and exhibits effective cytotoxicity against cervical cancer cells. Our results reveal that PACMA 31 selectively inhibits TrxR over the related glutathione reductase (GR) and in the presence of reduced glutathione (GSH). Further studies with mutant enzyme and molecular docking suggest that the propynamide fragment of PACMA 31 interacts covalently with the selenocysteine residue of TrxR. Moreover, PACMA 31 effectively and selectively curbs TrxR activity in cells and further stimulates the production of reactive oxygen species (ROS) at low micromolar concentrations, which in turn triggers the accumulation of oxidized thioredoxin (Trx) and GSSG in cells. Follow-up studies demonstrate that PACMA 31 targets TrxR in cells to induce oxidative stress-mediated cancer cell apoptosis. Our results provide a new structural type of TrxR inhibitor that may serve as a useful probe for investigating the biology of TrxR-implicated pathways, and uncover a new target of PACMA 31 that contributes to it becoming a candidate for cancer treatment.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular , Neoplasias , Reductasa de Tiorredoxina-Disulfuro , Humanos , Apoptosis , Inhibidores Enzimáticos/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Reductasa de Tiorredoxina-Disulfuro/farmacología , Tiorredoxinas/metabolismoRESUMEN
Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty, and are an important source for innovative drugs and lead compounds. We present herein that natural product santamarine targeted thioredoxin reductase (TrxR) to weaken its antioxidative function in cells, accompanied by accumulation of high levels of reactive oxygen species (ROS), and finally induced a new mechanism of tumor cell oxidative stress-mediated apoptosis. TrxR knockdown or overexpression cell lines were employed to further evaluate the cytotoxicity of santamarine regulated by TrxR, demonstrated that TrxR played a key role in the physiological effect of santamarine on cells. Santamarine targeting TrxR reveals its previously unrecognized mechanism of antitumor and provides a basis for the further development of santamarine as a potential cancer therapeutic agent.
RESUMEN
Upregulation of the selenoprotein thioredoxin reductase (TrxR) is of pathological significance in maintaining tumor phenotypes. Thus, TrxR inhibitors are promising cancer therapeutic agents. We prepared different amino-substituted phenylarsine oxides and evaluated their cytotoxicity and inhibition of TrxR. Compared with our reported p-substituted molecule (8), the o-substituted molecule (10) shows improved efficacy (nearly a fourfold increase) to kill leukemia HL-60 cells. Although the compounds 8 and 10 display similar potency to inhibit the purified TrxR, the o-substitution 10 exhibits higher potency than the p-substitution 8 to inhibit the cellular TrxR activity. Molecular docking results demonstrate the favorable weak interactions of the o-amino group with the TrxR C-terminal active site. Efficient inhibition of TrxR consequently induces the oxidative stress-mediated apoptosis of cancer cells. Silence of the TrxR expression sensitizes the cells to the arsenic compound treatment, further supporting the critical involvement of TrxR in the cellular actions of compound 10.
Asunto(s)
Antineoplásicos/uso terapéutico , Arsenicales/farmacología , Leucemia/tratamiento farmacológico , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Arsenicales/química , Células HL-60 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT-Se3 and CPT-Se4) were identified to show improved potency in killing cancer cells and inhibiting tumor growth in vivo. Interestingly, the intrinsic fluorescence of CPT was severely quenched by the diselenide bond. Both the selenoprodrugs were activated by glutathione with a nearly complete recovery of CPT's fluorescence. The activation of prodrugs was accompanied by the production of selenol intermediates, which catalyzed the constant conversion of glutathione and oxygen to oxidized glutathione and superoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored in the activation process prior to this study. Our work verified that integration of the diselenide unit may further enhance the parent drug's efficacy. Also, the discovery of the fluorescence quenching property of the diselenide/disulfide bond further shed light on constructing novel theranostic agents.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/química , Camptotecina/farmacología , Proliferación Celular/efectos de los fármacos , Colorantes Fluorescentes/química , Profármacos/síntesis química , Compuestos de Selenio/química , Inhibidores de Topoisomerasa I/farmacología , Animales , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Glutatión/metabolismo , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Imagen Óptica , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor controlling a series of cytoprotective genes, is closely associated with scavenging the reactive oxygen species and maintaining the intracellular redox balance. Accumulating evidence has indicated that activation of Nrf2 is efficient to block or retard oxidative stress mediated neurodegenerative disorders. Small molecules that contribute directly or indirectly to the Nrf2 activation thus are promising therapeutic agents. Herein, we screened xanthohumol and its analogues, and two analogues (11 and 12) were disclosed to possess low cytotoxicity and rescue PC12 cells from the hydrogen peroxide or 6-hydroxydopamine induced injuries. Molecular mechanism studies demonstrated that compounds 11 and 12 are potent Nrf2 activators by promoting the nuclear accumulation of Nrf2 and enhancing the cellular antioxidant defense system. More importantly, genetically silencing the Nrf2 expression shuts down the observed cytoprotection conferred by both compounds, supporting the critical involvement of Nrf2 for the cellular actions of compounds 11 and 12.
Asunto(s)
Flavonoides/farmacología , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Propiofenonas/farmacología , Animales , Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/metabolismo , Células PC12 , Ratas , Especies Reactivas de OxígenoRESUMEN
A pair of enantiomeric polyketides, (+)- and (-)-alternamgin (1), featuring an unprecedented 6/6/6/6/5/6/6 seven ring backbone, were isolated from the endophytic fungi Alternaria sp. MG1. The relative configuration of 1 was determined using X-ray diffraction, and the absolute configurations of (±)-1 were confirmed by comparing the experimental and calculated ECD data. Plausible biosynthetic pathways for 1 were proposed. Compound (-)-1 exhibited moderate necrosis rates to Hela and HepG2 cells, but (+)-1 only showed similar necrosis rates to HepG2 cells.