RESUMEN
The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.
Asunto(s)
Glioblastoma , Glioma , Humanos , Proteína p53 Supresora de Tumor/genética , Glioma/tratamiento farmacológico , Glioma/genética , Apoptosis , Células Madre Neoplásicas , Proteínas Proto-Oncogénicas c-mdm2/genéticaRESUMEN
For adult women in the United States, breast cancer is the most prevalent form of cancer. Compounds that target dysregulated signal transduction can be efficacious anti-cancer therapies. A prominent signaling pathway frequently dysregulated in breast cancer cells is the Wingless-related integration site (Wnt) pathway. The purpose of the work was to optimize a "hit" from a screening campaign. 76,000 compounds were tested in a Wnt transcription assay and revealed potent and reproducible "hit," compound 1. Medicinal chemistry optimization of 1 led to more potent and drug-like molecules, 19, 24 and 25 (i.e., Wnt pathway IC50 valuesâ¯=â¯11, 18 and 7â¯nM, respectively). The principal results showed compounds 19, 24 and 25 were potent anti-proliferative agents in breast cancer cell lines, MCF-7 (i.e., IC50 valuesâ¯=â¯10, 7 and 4â¯nM, respectively) and MDA-MB 231 (i.e., IC50 valuesâ¯=â¯13, 13 and 16â¯nM, respectively). Compound 19 synergized anti-proliferation with chemotherapeutic Doxorubicin in vitro. A major conclusion was that compound 19 enhanced anti-proliferation of Doxorubicin in vitro and in a xenograft animal model of breast cancer.
Asunto(s)
Antineoplásicos/química , Sulfonamidas/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Ratones , Ratones Desnudos , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Transcripción Genética/efectos de los fármacos , Trasplante Heterólogo , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMEN
Regulatory T cells (Tregs) have critical roles in maintaining immune hemostasis and have important anti-inflammatory functions in diseases. Recently, we identified that CX-5461 (a selective RNA polymerase I inhibitor and p53 activator) acted as a potent immunosuppressive agent, which prevented allogeneic acute rejection in animal models via a molecular mechanism distinct from all those of conventional immunosuppressive drugs. Unexpectedly, we discovered that CX-5461 could promote Treg differentiation. In this review, we have summarized the evidence for a potential role of p53 in mediating Treg differentiation and its possible mechanisms, including regulation of FoxP3 transcription, regulation of the expression of PTEN (phosphatase and tensin homolog), as well as protein-protein interaction with the transcription factor STAT5 (signal transducer and activator of transcription 5). Evidence also suggests that pharmacological p53 activators may potentially be used to boost Treg-mediated immune tolerance. Based on these data, we argue that novel p53 activators such as CX-5461 may represent a distinct class of immunosuppressants that repress conventional T cell-mediated alloimmunity with concomitant boosting of Treg-dependent immune tolerance.
Asunto(s)
Linfocitos T Reguladores , Proteína p53 Supresora de Tumor , Animales , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Tolerancia Inmunológica , Regulación de la Expresión Génica , Factores de Transcripción Forkhead/metabolismoRESUMEN
Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.
Asunto(s)
Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Pirroles/farmacología , Tiazoles/farmacología , Proteína p53 Supresora de Tumor/genética , Animales , Antineoplásicos/síntesis química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Doxorrubicina/farmacología , Descubrimiento de Drogas , Sinergismo Farmacológico , Femenino , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Unión Proteica , Pirroles/síntesis química , Tiazoles/síntesis química , Proteína p53 Supresora de Tumor/agonistas , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
It is highly desirable to activation p53 function with small-molecule compounds for colon cancer therapy. Triterpene saponin has been characterized with the favorable selectivity and safety profiles. However, the application of triterpene saponin as cancer chemotherapy drugs was hampered primarily by moderate anticancer potency and the lack the mechanism of action. In this study, we synthesized a series of Albiziabioside A derivatives and evaluated the antitumor activity both in vitro and in vivo. Compounds D13 possessed strong inhibitory activity against HCT116â¯cells with IC50 values of 5.19⯵M. More importantly, compound D13 had a favorable selectivity and was efficacious against MDR cancer cells. Moreover, compound D13 could induce apoptosis and ferroptosis through the mitochondrial pathway as a p53 activator. In addition, compound D13 significantly suppressed tumorigenesis without inducing toxicity in normal organs in vivo. Collectively, this study provides a clinically relevant argument for considering triterpene saponin derivatives D13 as potential cancer therapeutic candidates with enhanced activity, acceptable safety and novel mechanisms of action. To the best of our knowledge, this compound is the first drug candidate which can induce apoptosis and ferroptosis as a p53 activator.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Productos Biológicos/farmacología , Hierro/metabolismo , Mitocondrias/efectos de los fármacos , Saponinas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Saponinas/síntesis química , Saponinas/química , Relación Estructura-ActividadRESUMEN
Developing a sophisticated nanomedicine platform to deliver therapeutics effectively and safely into tumor/cancer cells remains challenging in the field of nanomedicine. In particular, reliable peptide drug delivery systems capable of overcoming biological barriers are still lacking. Here, we developed a simple, rapid, and robust strategy to manufacture nanoclusters of â¼90 nm in diameter that are self-assembled from lanthanide-doped nanoparticles (5 nm), two anticancer peptides with different targets (BIM and PMI), and one cyclic peptide iNGR targeted to cancer cells. The peptide-lanthanide nanoclusters (LDC-PMI-BIM-iNGR) enhanced the resistance of peptide drugs to proteolysis, disassembled in response to reductive conditions that are present in the tumor microenvironment and inhibited cancer cell growth in vitro and in vivo. Notably, LDC-PMI-BIM-iNGR exhibited extremely low systemic toxicity and side effects in vivo. Thus, the peptide-lanthanide nanocluster may serve as an ideal multifunctional platform for safe, targeted, and efficient peptide drug delivery in cancer therapy.