RESUMEN
Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Quinolinas , Receptores de Estrógenos , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/química , Quinolinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Receptores de Estrógenos/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Animales , Muerte Celular Inmunogénica/efectos de los fármacos , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Células MCF-7 , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacosRESUMEN
A drug conjugate consists of a cytotoxic drug bound via a linker to a targeted ligand, allowing the targeted delivery of the drug to one or more tumor sites. This approach simultaneously reduces drug toxicity and increases efficacy, with a powerful combination of efficient killing and precise targeting. Antibodyâdrug conjugates (ADCs) are the best-known type of drug conjugate, combining the specificity of antibodies with the cytotoxicity of chemotherapeutic drugs to reduce adverse reactions by preferentially targeting the payload to the tumor. The structure of ADCs has also provided inspiration for the development of additional drug conjugates. In recent years, drug conjugates such as ADCs, peptideâdrug conjugates (PDCs) and radionuclide drug conjugates (RDCs) have been approved by the Food and Drug Administration (FDA). The scope and application of drug conjugates have been expanding, including combination therapy and precise drug delivery, and a variety of new conjugation technology concepts have emerged. Additionally, new conjugation technology-based drugs have been developed in industry. In addition to chemotherapy, targeted therapy and immunotherapy, drug conjugate therapy has undergone continuous development and made significant progress in treating lung cancer in recent years, offering a promising strategy for the treatment of this disease. In this review, we discuss recent advances in the use of drug conjugates for lung cancer treatment, including structure-based drug design, mechanisms of action, clinical trials, and side effects. Furthermore, challenges, potential approaches and future prospects are presented.
RESUMEN
A terbium(III) complex-based time-resolved luminescence probe for selenocysteine can inhibit selenoprotein activity via a selenolate-triggered cleavage reaction of sulfonamide bonds in living cells.
Asunto(s)
Selenocisteína , Terbio , Terbio/química , Luminiscencia , SelenoproteínasRESUMEN
Induction of immunogenic cell death (ICD) and activation of the cyclic GMP-AMP synthase stimulator of interferon gene (cGAS-STING) pathway are two potent anticancer immunotherapeutic strategies in hepatocellular carcinoma (HCC). Herein, 12 liver- and mitochondria-targeting gold(I) complexes (9a-9l) were designed and synthesized. The superior complex 9b produced a considerable amount of reactive oxygen species (ROS) and facilitated DNA excretion, the ROS-induced ICD and DNA activated the cGAS-STING pathway, both of which evoked an intense anticancer immune response in vitro and in vivo. Importantly, 9b strongly inhibited tumor growth in a patient-derived xenograft model of HCC. Overall, we present the first case of simultaneous ICD induction and cGAS-STING pathway activation within the same gold-based small molecule, which may provide an innovative strategy for designing chemoimmunotherapies for HCC.
Asunto(s)
Carcinoma Hepatocelular , Oro , Muerte Celular Inmunogénica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , ADN/metabolismo , Muerte Celular Inmunogénica/efectos de los fármacos , Inmunoterapia , Interferones , Neoplasias Hepáticas/tratamiento farmacológico , Mitocondrias/metabolismo , Nucleotidiltransferasas/metabolismo , Especies Reactivas de Oxígeno , Transducción de Señal , Oro/farmacología , Oro/uso terapéutico , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéuticoRESUMEN
Overexpression of the epidermal growth factor receptor (EGFR, erbB1) has been observed in a wide range of solid tumors and has frequently been associated with poor prognosis. As a result, EGFR inhibition has become an attractive anticancer drug design strategy, and a large number of small molecular inhibitors have been developed. Despite the widespread clinical use of EGFR tyrosine kinase inhibitors (TKIs), their drug resistance, inadequate accumulation in tumors, and severe side effects have spurred the search for better antitumor drugs. Metal complexes have attracted much attention because of their different mechanisms compared with EGFR-TKIs. Therefore, the combination of metals and inhibitors is a promising anticancer strategy. For example, Ru and Pt centers are introduced to design complexes with double or multiple targets, while Au complexes are combined with inhibitors to overcome drug resistance. Co complexes are designed as prodrugs with weak side effects and enhanced targeting by the hypoxia activation strategy, and other metals such as Rh and Fe enhance the anticancer effect of the complexes. In addition, the introduction of Ga center is beneficial to the development of nuclear imaging tracers. In this paper, metal EGFR-TKI complexes in the last 15 years are reviewed, their mechanisms are briefly introduced, and their advantages are summarized.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Receptores ErbB , Inhibidores de Proteínas Quinasas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Ligandos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
Inflammation contributes to the development of ovarian cancer, and chemoresistance is a principal obstacle in ovarian cancer treatment. Herein, we designed and synthesized a series of gold(I) complexes derived from NSAIDs or their analogues. Among them, complex B3 (Npx-Au) displayed higher antitumor activity than cisplatin and other gold(I) complexes. Npx-Au could induce oxidative stress and the damage-associated molecular patterns (DAMPs) process by the inhibition of TrxR activity. Mechanistic studies revealed that simultaneous downregulation of COX-2 and PD-L1 was observed after Npx-Au treatment. Interestingly, in vivo experiments demonstrated that Npx-Au treatment could stimulate the immune response via reducing the expression of PD-L1, inducing DC maturation and increasing the infiltration of T (CD4+ and CD8+) cells. Collectively, our studies found that the gold(I) complex Npx-Au could elicit immunogenic cell death (ICD) and provide a promising strategy for chemotherapy combined with immunotherapy in the treatment of ovarian cancer.
Asunto(s)
Antígeno B7-H1 , Neoplasias Ováricas , Humanos , Femenino , Especies Reactivas de Oxígeno , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Inmunidad , Oro , Inflamación/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Flúor/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Antagonistas de Estrógenos/farmacologíaRESUMEN
The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Antagonistas de Estrógenos/uso terapéutico , Muerte Celular Inmunogénica , Especies Reactivas de Oxígeno/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Compuestos Organometálicos/farmacología , Oro/químicaRESUMEN
Breast cancer is the most prevalent cancer in women and represents a serious disease that is harmful to life and health. In 1977, with the approval of tamoxifen, endocrine therapy has become the main clinical treatment for ER-positive (ER+) breast cancer. Although patients initially respond well to endocrine therapies, drug resistance often emerges and side effects can be challenging. To overcome drug resistance, the exploration for new drugs is a priority. Metal complexes have demonstrated significant antitumor activities, and platinum complexes are widely used in the clinic against various cancers, including breast cancer. In this Perspective, the first section describes the classification and mechanism of endocrine therapy drugs for ER+ breast cancer, and the second section summarizes research since 2000 into metal complexes with activity toward ER+ breast cancer. Finally, we discuss the opportunities, challenges, and future directions for metal complexes in the treatment of ER+ breast cancer.
Asunto(s)
Neoplasias de la Mama , Complejos de Coordinación , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Complejos de Coordinación/uso terapéutico , Tamoxifeno/uso terapéutico , Resistencia a Antineoplásicos , Antineoplásicos Hormonales/uso terapéuticoRESUMEN
Immunogenic cell death (ICD) is a promising direction of cancer immunotherapy in hepatocellular carcinoma (HCC). A series of novel NHC-Au(I) complexes derived from 4,5-diarylimidazole, containing glycyrrhetinic acid (GA) as an efficient targeting ligand for HCC, were herein designed and synthesized. Among these, complex 4C exhibited excellent effectiveness for tumor targeting and antitumor activity, which induced the occurrence of ICD in HCC cells. Additionally, 4C can effectively inhibit TrxR enzyme activity, increase reactive oxygen species (ROS) expression, lead to redox homeostasis disorder, mediate mitochondrial dysfunction and endoplasmic reticulum stress (ERS), and cause the characteristic discharge of damage-associated molecular patterns (DAMPs) in HCC cells. More importantly, 4C showed a great ICD-inducing effect in a vaccination mouse model and activated antitumor immunity in a tumor-bearing C57BL/6 mouse model, which is consistent with the in vitro results. In conclusion, we found the potential of Au(I) complex with HCC-targeted capability for effective tumor immunotherapy.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratones , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Muerte Celular Inmunogénica , Proliferación Celular , Ratones Endogámicos C57BL , Línea Celular TumoralRESUMEN
Multidrug-resistant (MDR) Gram-negative bacteria have become a global threat to human life and health, and novel antibiotics are urgently needed. The thioredoxin (Trx) system can be used as an antibacterial target to combat MDR bacteria. Here, we found that two active gold(I) selenium N-heterocyclic carbene complexes H7 and H8 show more promising antibacterial effects against MDR bacteria than auranofin. Both H7 and H8 irreversibly inhibit the bacterial TrxR activity via targeting the redox-active motif, abolishing the capacity of TrxR to quench reactive oxygen species (ROS) and finally leading to oxidative stress. The increased cellular superoxide radical levels impact a variety of functions necessary for bacterial survival, such as cellular redox balance, cell membrane integrity, amino acid metabolism, and lipid peroxidation. In vivo data present much better antibacterial activity of H7 and H8 than auranofin, promoting the wound healing and prolonging the survival time of Carbapenem-resistant Acinetobacter baumannii (CRAB) induced peritonitis. Most notably in this study, we revealed the influence of gold(I) complexes on both the Trx system and the cellular metabolic states to better understand their killing mechanism and to support further antibacterial drug design.
Asunto(s)
Oro , Selenio , Humanos , Oro/farmacología , Oro/química , Reductasa de Tiorredoxina-Disulfuro , Auranofina/farmacología , Auranofina/química , Selenio/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Bacterias/metabolismo , Bacterias Gramnegativas/metabolismoRESUMEN
Biosynthetic gene clusters (BGCs) are regions of a genome where genes involved in a biosynthetic pathway are in proximity. The origin and evolution of plant BGCs as well as their role in specialized metabolism remain largely unclear. In this study, we have assembled a chromosome-scale genome of Japanese catnip (Schizonepeta tenuifolia) and discovered a BGC that contains multiple copies of genes involved in four adjacent steps in the biosynthesis of p-menthane monoterpenoids. This BGC has an unprecedented bipartite structure, with mirrored biosynthetic regions separated by 260 kilobases. This bipartite BGC includes identical copies of a gene encoding an old yellow enzyme, a type of flavin-dependent reductase. In vitro assays and virus-induced gene silencing revealed that this gene encodes the missing isopiperitenone reductase. This enzyme evolved from a completely different enzyme family to isopiperitenone reductase from closely related Mentha spp., indicating convergent evolution of this pathway step. Phylogenomic analysis revealed that this bipartite BGC has emerged uniquely in the S. tenuifolia lineage and through insertion of pathway genes into a region rich in monoterpene synthases. The cluster gained its bipartite structure via an inverted duplication. The discovered bipartite BGC for p-menthane biosynthesis in S. tenuifolia has similarities to the recently described duplicated p-menthane biosynthesis gene pairs in the Mentha longifolia genome, providing an example of the convergent evolution of gene order. This work expands our understanding of plant BGCs with respect to both form and evolution, and highlights the power of BGCs for gene discovery in plant biosynthetic pathways.
Asunto(s)
Lamiaceae , Familia de Multigenes , Monoterpenos , CromosomasRESUMEN
Traditional platinum-based anticancer drugs, led by cisplatin, play an important role in chemotherapy. However, the development of platinum compounds is limited due to serious toxicity and side effects. In recent years, studies have showed that immunogenic cell death (ICD) may be one of the potential action mechanisms of classical platinum drugs, such as oxaliplatin. This strategy combining chemotherapy and immunotherapy can effectively utilize the body's immune system to help platinum compounds to fight against tumors, and the dose can be appropriately reduced to limit toxic side effects. The induction of ICD by platinum compounds has become a research hotspot and one of the future development directions of metal drugs. Here, the progress of platinum compounds were collected and comprehensively summarized, their capacity of ICD induction and mechanism of action are exposed, providing reference for the design and synthesis of new anticancer platinum ICD inducers.
Asunto(s)
Antineoplásicos , Platino (Metal) , Platino (Metal)/farmacología , Muerte Celular Inmunogénica , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cisplatino/farmacología , Compuestos de Platino/farmacología , Compuestos de Platino/uso terapéuticoRESUMEN
Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented.
Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Oro/química , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
The nonnegligible reason for the poor prognosis of hepatocellular carcinoma (HCC) is resistance to conventional chemotherapy. Immunogenic cell death (ICD) is a rare immunostimulatory form of cell death that can reengage the tumor-specific immune system. ICD can improve the clinical outcomes of chemotherapeutics by promoting a long-term cancer immunity. The discovery of potential ICD inducers is emerging as a promising direction. In the present study, micheliolide (MCL), a natural guaianolide sesquiterpene lactone, was screened out by the virtual screening strategies, identified as an inhibitor of thioredoxin reductase (TrxR) and was evaluated to have high potential to induce ICD. Here, we showed that MCL induced ICD-associated DAMPs (damage-associated molecular patterns, such as CRT exposure, ATP secretion and HMGB1 release). MCL significantly triggered the regression of established tumors in an immunocompetent mouse vaccine model, and induced ICD (DCs maturation, the stimulation of CD4+, and CD8+ T-cells responses) in vivo. Mechanistically, we found that the magnitude of ICD-associated effects induced upon exposure of HCC cells to MCL was dependent on the generation of reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ERS). In addition, the suppression of ROS normalized MCL-induced ERS, in contrast, the downregulation of TrxR synergized with the ERS driven by MCL. We also systematically detected the H2O2 generation using Hyper7 sensors in HCC cells exposed to MCL. Notably, MCL inhibited the development of HCC organoids. Collectively, our results reveal a potential association between the TrxR inhibitors and ICD, presenting valuable insights into the MCL-activated ICD in HCC cells.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Estrés del Retículo Endoplásmico , Peróxido de Hidrógeno/farmacología , Muerte Celular Inmunogénica , Neoplasias Hepáticas/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo , Reductasa de Tiorredoxina-DisulfuroRESUMEN
The search for highly selective sensitizers with a novel mechanism for tumor targeting therapy is of considerable interest. In this work, we have developed a series of new biotin-targeted Au(I) complexes. Through systematic biological evaluation and comparison, biotinylated Au(I) complex 3a containing a triphenylphosphine ligand was screened, as it realized both prominent efficient inhibition and selective cytotoxicity to cancer cells, and the effect was better than that of popularly used auranofin. Meanwhile, complex 3a, as a potent radiosensitizer, enhances anticancer effects in vitro and in vivo and has sensitization selectivity. From the action mechanism study, we provide evidence that complex 3a could intervene in redox homeostasis through targeted binding and strong suppression of thioredoxin reductase (TrxR) and induce the ferroptosis death process, enabling it to sensitize tumor cells to radiotherapy. Thus, complex 3a has enormous potential as an efficient and specific radiosensitizing agent in cancer therapy.
Asunto(s)
Antineoplásicos , Ferroptosis , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Auranofina/farmacología , Biotina/metabolismo , Biotina/farmacología , Línea Celular Tumoral , Homeostasis , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oxidación-Reducción , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
Endometrial cancer (EC), one of the most common gynaecologic malignancies, can seriously impair female health. Although great advances in EC therapy have been achieved, specific and effective drugs for the disease are still limited. Here, different types of gold(I)-NHC compounds originated from 4,5-bis (4-methoxyphenyl) imidazole were designed and synthesised to target EC. Interestingly, the heteroleptic gold(I)-bisNHC complex 10 was 10 times more toxic than cisplatin or auranofin towards Ishikawa cells. Ex vivo studies found that complex 10 was characterised with a stronger anticancer effect than auranofin in the EC organoid model. Additionally, in vivo studies showed that complex 10 possessed a stronger anticancer effect (IRT = 44.86%) than auranofin (IRT = 19.93%) in the xenograft model of EC. Mechanistically, complex 10 could suppress the expression of thioredoxin reductase (TrxR) and nuclear factor E2-related factor 2 (Nrf2) in vitro and in vivo, which are essentially involved in EC development. Collectively, our findings demonstrated that complex 10 is a gold-based complex with a strong anti-EC activity and has the potential to be regarded as a promising option for the treatment of EC.
Asunto(s)
Neoplasias Endometriales , Oro , Auranofina/farmacología , Cisplatino , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Oro/farmacología , Humanos , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
Multidrug resistance (MDR) is a significant issue associated with the clinical application of antibiotics. It is also challenging to discover and develop new antibiotics with novel scaffolds. Therefore, the repurposing of existing drugs has become a promising strategy for antibiotic drug discovery. Auranofin, an approved gold metallic drug, has been used for the treatment of rheumatoid arthritis (RA) for many years. Recent research revealed that auranofin has strong antibacterial activity against multiple Gram-positive bacteria by inhibiting thioredoxin reductase (TrxR). These results inspired the development of gold complexes as antibacterial agents. Herein, we discuss recent advances in the development of auranofin and other gold complexes as antibacterial agents, providing a new viewpoint for the treatment of bacterial infection.
Asunto(s)
Auranofina , Reposicionamiento de Medicamentos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Auranofina/farmacología , Auranofina/uso terapéutico , Oro , Reductasa de Tiorredoxina-DisulfuroRESUMEN
The upregulation of lipid metabolism is considered one of the most common characteristic changes in tumor cells. In this study, the effects of phosphanegold(I) thiolate complexes on the regulation of lipid metabolism in lung cancer cells were investigated. Six novel phosphanegold(I) thiolate complexes capable of inhibiting lung cancer cell growth both in vitro and in vivo were synthesized and characterized. These complexes significantly inhibited the activity of thioredoxin reductases and impaired the normal structure and function of mitochondria, leading to an accumulation of internal reactive oxygen species. In addition, they markedly inhibited key enzymes involved in de novo lipid synthesis, including sterol regulatory element-binding proteins, fatty acid synthase, and adenosine triphosphate citrate lyase, thus reducing endogenous fatty acid and phospholipid synthesis. Both approaches suppressed lipid droplets storage and ultimately induced apoptosis in lung cancer cells. Interestingly, pretreatment with N-acetyl-l-cysteine and free fatty acids partially reversed the inhibitory effect of phosphanegold(I) thiolate complexes on lung cancer cells. These results are the first to indicated that gold(I) complexes are promising candidates for targeting lipid metabolism in lung cancer treatment strategies.
Asunto(s)
Lipogénesis , Neoplasias Pulmonares , Línea Celular Tumoral , Ácidos Grasos/metabolismo , Humanos , Metabolismo de los Lípidos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Immunogenic cell death (ICD) can engage a specific immune response and establish a long-term immunity in hepatocellular carcinoma (HCC). Herein, we design and synthesize a series of Pt(II)-N-heterocyclic carbene (Pt(II)-NHC) complexes derived from 4,5-diarylimidazole, which show strong anticancer activities in vitro. Among them, 2c displays much higher anticancer activities than cisplatin and other Pt(II)-NHC complexes, especially in HCC cancer cells. In addition, we find that 2c is a type II ICD inducer, which can successfully induce endoplasmic reticulum stress (ERS) accompanied by reactive oxygen species (ROS) generation and finally lead to the release of damage-associated molecular patterns (DAMPs) in HCC cells. Importantly, 2c shows a great anti-HCC potential in a vaccination mouse model and leads to the in vivo immune cell activation in the CCl4-induced liver injury model.