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Ferroptosis is a novel form of programmed cell death morphologically, genetically, and biochemically distinct from other cell death pathways and characterized by the accumulation of iron-dependent lipid peroxides and oxidative damage. It is now understood that ferroptosis plays an essential role in various biological processes, especially in the metabolism of iron, lipids, and amino acids. Gastric cancer (GC) is a prevalent malignant tumor worldwide with low early diagnosis rates and high metastasis rates, accounting for its relatively poor prognosis. Although chemotherapy is commonly used to treat GC, drug resistance often leads to poor therapeutic outcomes. In the last several years, extensive research on ferroptosis has highlighted its significant potential in GC therapy, providing a promising strategy to address drug resistance associated with standard cancer therapies. In this review, we offer an extensive summary of the key regulatory factors related to the mechanisms underlying ferroptosis. Various inducers and inhibitors specifically targeting ferroptosis are uncovered. Additionally, we explore the prospective applications and outcomes of these agents in the field of GC therapy, emphasizing their capacity to improve the outcomes of this patient population.
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Ferroptose , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Aminoácidos , Apoptose , FerroRESUMO
BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve GAC patients poses a significant challenge, limiting the scope of current research, which has predominantly focused on localized tumors. This gap hinders a deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary-metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment (TME) during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, employing cell lines, multiple PDX and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of TME phenotypes, supporting the notion that cancer cells and their local TMEs co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 upregulation during GAC progression. Conditional depletion of Gpx4 or pharmacological inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. Additionally, ferroptosis-resensitizing treatments augmented the efficacy of CAR T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with CAR T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.
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Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
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Células Apresentadoras de Antígenos , Vacinas Anticâncer , Imunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Nanopartículas/administração & dosagem , Células Apresentadoras de Antígenos/imunologia , Biomimética/métodos , Materiais Biomiméticos/administração & dosagem , Animais , Lipossomos , NanovacinasRESUMO
Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.
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Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/radioterapia , Radioisótopos do Iodo/uso terapêutico , Transdução de SinaisRESUMO
As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.
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Quimera de Direcionamento de Proteólise , Humanos , Cinética , MutaçãoRESUMO
OBJECTIVE: Metabolic biomarkers are expected to decode the phenotype of gastric cancer (GC) and lead to high-performance blood tests towards GC diagnosis and prognosis. We attempted to develop diagnostic and prognostic models for GC based on plasma metabolic information. DESIGN: We conducted a large-scale, multicentre study comprising 1944 participants from 7 centres in retrospective cohort and 264 participants in prospective cohort. Discovery and verification phases of diagnostic and prognostic models were conducted in retrospective cohort through machine learning and Cox regression of plasma metabolic fingerprints (PMFs) obtained by nanoparticle-enhanced laser desorption/ionisation-mass spectrometry (NPELDI-MS). Furthermore, the developed diagnostic model was validated in prospective cohort by both NPELDI-MS and ultra-performance liquid chromatography-MS (UPLC-MS). RESULTS: We demonstrated the high throughput, desirable reproducibility and limited centre-specific effects of PMFs obtained through NPELDI-MS. In retrospective cohort, we achieved diagnostic performance with areas under curves (AUCs) of 0.862-0.988 in the discovery (n=1157 from 5 centres) and independent external verification dataset (n=787 from another 2 centres), through 5 different machine learning of PMFs, including neural network, ridge regression, lasso regression, support vector machine and random forest. Further, a metabolic panel consisting of 21 metabolites was constructed and identified for GC diagnosis with AUCs of 0.921-0.971 and 0.907-0.940 in the discovery and verification dataset, respectively. In the prospective study (n=264 from lead centre), both NPELDI-MS and UPLC-MS were applied to detect and validate the metabolic panel, and the diagnostic AUCs were 0.855-0.918 and 0.856-0.916, respectively. Moreover, we constructed a prognosis scoring system for GC in retrospective cohort, which can effectively predict the survival of GC patients. CONCLUSION: We developed and validated diagnostic and prognostic models for GC, which also contribute to advanced metabolic analysis towards diseases, including but not limited to GC.
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Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (Kd= 3.29 µM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 µΜ. XYA-2 at 1 µΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.
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Neoplasias Gástricas , Humanos , Animais , Camundongos , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fosforilação , Proliferação de Células , ApoptoseRESUMO
Ferroptosis is a new type of regulated, non-apoptotic cell death driven by iron-dependent phospholipid peroxidation. Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) has been considered as an effective cancer treatment strategy, but only few GPX4 inhibitors have been reported to date. Targeted protein degradation is receiving increasing attention in the discovery and development of therapeutic modality, particularly proteolysis targeting chimeras (PROTACs). Herein, we reported the design, synthesis, and evaluation of different types of GPX4-targeting PROTACs using ML162 derivatives and ligands for CRBN/VHL E3 ligases. Among them, CRBN-based PROTAC GDC-11 showed a relatively balanced biological profile in GPX4 degradation (degradation rate of 33% at 10 µM), cytotoxicity (IC50 = 11.69 µM), and lipid peroxides accumulation (2-foldincreaserelatedtoDMSO), suggesting a typical characteristic of ferroptosis. In silico docking and quantum chemistry theoretical calculations provided a plausible explanation for the moderate degrading effect of these synthesized PROTACs. Overall, this work lays the foundation for subsequent studies of GPX4-targeting PROTACs, and further design and synthesis of GPX4-targeting degrader are currently in progress in our group, which will be reported in due course.
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Ferro , Peróxidos Lipídicos , Proteólise , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Peróxidos , Quimera de Direcionamento de ProteóliseRESUMO
Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.
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Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Resistência a Medicamentos , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. METHODS: Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. RESULTS: UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. CONCLUSIONS: These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.
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Neoplasias Pancreáticas , Enzimas de Conjugação de Ubiquitina , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , NF-kappa B/metabolismo , Neoplasias Pancreáticas/patologia , Proteômica , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias PancreáticasRESUMO
Signal transducer and activator of transcription 3 (STAT3) plays a critical role in signal transmission from the plasma membrane to the nucleus, regulating the expression of genes involved in essential cell functions and controlling the processes of cell cycle progression and apoptosis. Thus, STAT3 has been elucidated as a promising target for developing anticancer drugs. Many natural products have been reported to inhibit the STAT3 signaling pathway during the past two decades and have exhibited significant anticancer activities in vitro and in vivo. However, there is no FDA-approved STAT3 inhibitor yet. The major mechanisms of these natural product inhibitors of the STAT3 signaling pathway include targeting the upstream regulators of STAT3, directly binding to the STAT3 SH2 domain and inhibiting its activation, inhibiting STAT3 phosphorylation and/or dimerization, and others. In the present review, we have systematically discussed the development of these natural product inhibitors of STAT3 signaling pathway as well as their in vitro and in vivo anticancer activity and mechanisms of action. Outlooks and perspectives on the associated challenges are provided as well.
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Produtos Biológicos , Neoplasias , Apoptose , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a key regulator of many human cancers and has been widely recognized as a promising target for cancer therapy. A variety of small-molecule inhibitors have been developed for targeting STAT3, and some of them are now undergoing clinical trials. S3I-201, a known STAT3 inhibitor, may block STAT3 function in cancer cells by binding to the STAT3 SH2 domain to disrupt STAT3 protein complex formation. Using S3I-201 as a starting point for drug development, we synthesized a series of new STAT3 inhibitors 9a-x in this study by introducing naphthoquinone unit, a privileged fragment in STAT3 inhibitors. Most of the compounds exhibited strong anti-proliferation activity of gastric cancer cells (MGC803, MKN28, MNK1, and AGS). The representative compound 9n (SIL-14) could effectively inhibit the colony formation and migration of gastric cancer cells MGC803, arrest the cell cycle and induce MGC803 cell apoptosis at low micromolar concentrations in vitro. In addition, SIL-14 can also inhibit the phosphorylation of STAT3 protein and significantly decrease the expression of total STAT3, suggesting that it may exert anticancer effects by blocking the STAT3 signaling pathway. These results support that SIL-14 may be a promising STAT3 inhibitor for the further development of potential anti-gastric cancer candidates.
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Naftoquinonas , Neoplasias Gástricas , Ácidos Aminossalicílicos/farmacologia , Ácidos Aminossalicílicos/uso terapêutico , Benzenossulfonatos , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
A new meroterpenoid, taladrimanin A (1), was isolated from a marine-derived fungus Talaromyces sp. HM6-1-1, together with eleven biogenetically related compounds (2-12). A plausible biosynthetic pathway for the meroterpenoids (1-4) was proposed. The planar structure of 1 was assigned by HRESIMS and NMR. Its relative configuration was established by quantum chemical NMR calculation of two possible isomers and analyzed by DP4 + method. Finally, X-ray diffraction unambiguously confirmed the relative configuration and revealed the absolute configuration of compound 1. 2-12 were assigned by comparing their NMR data with those reported in the literature. 1 was the first drimane-type meroterpenoid with a C10 polyketide unit bearing an 8R-configuration. In the bioactive assay, 1 exhibited antitumor activity against gastric cancer cells MGC803 and MKN28; it also inhibited the colony formation and induced apoptosis in MGC803 cells both in a concentration-dependent manner. Additionally, 1 displayed selective antibacterial activity against Staphylococcus aureus 6538P, and low activities towards strains of Vibrio parahaemolyticus and Escherichia coli in this study. KEY POINTS: ⢠Twelve compounds were obtained from Talaromyces sp., including four meroterpenoids, one of which was new. ⢠The new compound taladrimanin A (1) inhibits the growth of gastric cancer cells MGC803 and MKN28 as well as the pathogenic bacteria Staphylococcus aureus 6538P. ⢠The biosynthetic pathway of the meroterpenoids was proposed.
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Neoplasias Gástricas , Talaromyces , Antibacterianos/farmacologia , Escherichia coli , Humanos , Estrutura Molecular , Staphylococcus aureus , Talaromyces/químicaRESUMO
Gastric cancer remains a significant health burden worldwide. In continuation of our previous study and development of effective small molecules against gastric cancer, a series of benzochalcone analogues involving heterocyclic molecules were synthesised and biologically evaluated in vitro and in vivo. Among them, the quinolin-6-yl substituted derivative KL-6 inhibited the growth of gastric cancer cells (HGC27, MKN28, AZ521, AGS, and MKN1) with a submicromolar to micromolar range of IC50, being the most potent one in this series. Additionally, KL-6 significantly inhibited the colony formation, migration and invasion, and effectively induced apoptosis of MKN1 cells in a concentration-dependent manner. The mechanistic study revealed that KL-6 could concentration-dependently suppress STAT3 phosphorylation, which may partly contribute to its anticancer activity. Furthermore, in vivo antitumour study on the MKN1 orthotopic tumour model showed that KL-6 effectively inhibited tumour growth (TGI of 78%) and metastasis without obvious toxicity. Collectively, compound KL-6 may support the further development of candidates for gastric cancer treatment.
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Chalconas , Fator de Transcrição STAT3 , Neoplasias Gástricas , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/farmacologia , Humanos , Terapia de Alvo Molecular , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológicoRESUMO
The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.
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Adenocarcinoma/diagnóstico , Antineoplásicos/uso terapêutico , Misturas Complexas/uso terapêutico , Neoplasias Esofágicas/diagnóstico , Junção Esofagogástrica , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/metabolismo , Humanos , Masculino , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Análise Serial de Tecidos , Trametes , Resultado do TratamentoRESUMO
The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Química Farmacêutica , Desenho de Fármacos , Descoberta de Drogas , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/patologia , Relação Estrutura-AtividadeRESUMO
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
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Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Animais , Doenças Autoimunes/tratamento farmacológico , Biomarcadores/metabolismo , Demência/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Glomerulonefrite/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Oncologia/métodos , Camundongos , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Obesidade/tratamento farmacológico , Prognóstico , Ratos , Síndrome de Sjogren/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismoRESUMO
Gastric cancer is a deadly disease and remains the third leading cause of cancer-related death worldwide. The 5-year overall survival rate of patients with early-stage localized gastric cancer is more than 60%, whereas that of patients with distant metastasis is less than 5%. Surgical resection is the best option for early-stage gastric cancer, while chemotherapy is mainly used in the middle and advanced stages of this disease, despite the frequently reported treatment failure due to chemotherapy resistance. Therefore, there is an unmet medical need for identifying new biomarkers for the early diagnosis and proper management of patients, to achieve the best response to treatment. Long non-coding RNAs (lncRNAs) in body fluids have attracted widespread attention as biomarkers for early screening, diagnosis, treatment, prognosis, and responses to drugs due to the high specificity and sensitivity. In the present review, we focus on the clinical potential of lncRNAs as biomarkers in liquid biopsies in the diagnosis and prognosis of gastric cancer. We also comprehensively discuss the roles of lncRNAs and their molecular mechanisms in gastric cancer chemoresistance as well as their potential as therapeutic targets for gastric cancer precision medicine.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , RNA não Traduzido/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Animais , Progressão da Doença , Humanos , Medicina de Precisão , RNA não Traduzido/genética , Neoplasias Gástricas/genéticaRESUMO
Eight new nitrogenated azaphilones (1-8) and two known compounds (chaetoviridin A and chaetoviridin E, 9, 10) were isolated from the culture of the deep-sea-derived fungus Chaetomium globosum MP4-S01-7. The absolute configurations of new compounds were elucidated by HSQC-HECADE NMR data, J-based configuration analysis, and modified Mosher's method and finally verified by comparison of recorded and computed NMR chemical shifts from quantum chemical calculations coupled with a statistical procedure (DP4+). All of the compounds were evaluated for their in vitro cytotoxicities against the gastric cancer cell lines MGC803 and AGS, and most of them showed significant inhibition on cancer cell viability at 10 µM. Among them, compounds 1, 2, and 5 exerted the most potent cytotoxic activities, with IC50 values less than 1 µM. Further studies showed that compound 2 inhibited cell cycle progression, and both compounds 1 and 2 induced apoptosis of gastric cancer cells in a concentration-dependent manner.
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Antineoplásicos/farmacologia , Benzopiranos/toxicidade , Chaetomium/química , Pigmentos Biológicos/toxicidade , Antineoplásicos/química , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pigmentos Biológicos/química , Pigmentos Biológicos/farmacologiaRESUMO
A new dihydrobenzofuran-phenyl acrylate hybrid, aspeterreurone A (1), was obtained from the culture of the deep-sea-derived fungus Aspergillus terreus CC-S06-18. The relative configuration of 1 was elucidated by HSQMBC NMR, calculated NMR chemical shifts coupled with a statistical procedure (DP4+), and the absolute configuration was established by ECD calculations. 1 exhibited cytotoxicities against the gastric cancer cell lines HGC27, MGC803, BGC823, and AGS, with minimal effects on normal gastric epithelial cell line GES-1. Further studies showed that 1 inhibited cell cycle progression and induced apoptosis of gastric cancer MGC803 cells in a concentration-dependent manner. Western blot analysis indicated that 1 inhibited the phosphorylation of STAT3, which might contribute to its cytotoxic activity.