RESUMEN
The heterogeneity of hepatocellular carcinoma (HCC) can prevent effective treatment, emphasizing the need for more effective therapies. Herein, we employed arsenene nanosheets coated with manganese dioxide and polyethylene glycol (AMPNs) for the degradation of Pin1, which is universally overexpressed in HCC. By employing an "AND gate", AMPNs exhibited responsiveness toward excessive glutathione and hydrogen peroxide within the tumor microenvironment, thereby selectively releasing AsxOy to mitigate potential side effects of As2O3. Notably, AMPNs induced the suppressing Pin1 expression while simultaneously upregulation PD-L1, thereby eliciting a robust antitumor immune response and enhancing the efficacy of anti-PD-1/anti-PD-L1 therapy. The combination of AMPNs and anti-PD-1 synergistically enhanced tumor suppression and effectively induced long-lasting immune memory. This approach did not reveal As2O3-associated toxicity, indicating that arsenene-based nanotherapeutic could be employed to amplify the response rate of anti-PD-1/anti-PD-L1 therapy to improve the clinical outcomes of HCC patients and potentially other solid tumors (e.g., breast cancer) that are refractory to anti-PD-1/anti-PD-L1 therapy.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Compuestos de Manganeso , Peptidilprolil Isomerasa de Interacción con NIMA , Óxidos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Óxidos/química , Óxidos/farmacología , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Nanoestructuras/química , Antineoplásicos/química , Antineoplásicos/farmacología , Arsenicales/química , Arsenicales/farmacología , Arsenicales/uso terapéutico , Ratones , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Línea Celular Tumoral , Polietilenglicoles/químicaRESUMEN
Covalent peptide binders have found applications as activity-based probes and as irreversible therapeutic inhibitors. Currently, there is no rapid, label-free, and tunable affinity selection platform to enrich covalent reactive peptide binders from synthetic libraries. We address this challenge by developing a reversibly reactive affinity selection platform termed ReAct-ASMS enabled by tandem high-resolution mass spectrometry (MS/MS) to identify covalent peptide binders to native protein targets. It uses mixed disulfide-containing peptides to build reversible peptide-protein conjugates that can enrich for covalent variants, which can be sequenced by MS/MS after reduction. Using this platform, we identified covalent peptide binders against two oncoproteins, human papillomavirus 16 early protein 6 (HPV16 E6) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 protein (Pin1). The resulting peptide binders efficiently and selectively cross-link Cys58 of E6 at 37 °C and Cys113 of Pin1 at room temperature, respectively. ReAct-ASMS enables the identification of highly selective covalent peptide binders for diverse molecular targets, introducing an applicable platform to assist preclinical therapeutic development pipelines.
Asunto(s)
Péptidos , Péptidos/química , Proteínas Oncogénicas Virales/química , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/química , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Espectrometría de Masas en Tándem/métodos , Unión ProteicaRESUMEN
Juglone (5 - hydroxy - 1, 4 - naphthalene diketone) is a kind of natural naphthoquinone, present in the roots, leaves, nut-hulls, bark and wood of walnut trees. Recent studies have found that Juglone has special significance in the treatment of cancer, which plays a significant role in the resistance of cancer cell proliferation, induction of cancer cell apoptosis, induction of autophagy, anti-angiogenesis and inhibition of cancer cell migration and invasion, etc. Additionally, its derivatives also play a tumor suppressive effect. In conclusion, Juglone and its derivatives have been identified as effective anticancer drugs. This paper reviews action mechanisms of Juglone and its derivatives in cancer treatment.
Asunto(s)
Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Naftoquinonas/farmacología , Neoplasias/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/efectos de los fármacos , Humanos , Naftoquinonas/química , Neovascularización Patológica , Especies Reactivas de OxígenoRESUMEN
The unique proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is reported to activate numerous cancer-driving pathways simultaneously, and aberrant Pin1 activation is present in many human cancers. Here, we identified a novel hit compound, ZL-Pin01, that covalently modified Pin1 at Cys113 with an half-maximal inhibitory concentration (IC50) of 1.33 ± 0.07 µM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 ± 0.03 µM. We obtained four co-crystal structures of Pin1 complexed with inhibitors that elucidated the detailed binding mode of the derivatives with Pin1. Interestingly, the co-crystal of Pin1 with ZL-Pin13 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, ZL-Pin13 effectively inhibited the proliferation and downregulated the Pin1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of Pin1, ZL-Pin13, which could be an effective probe for studying the functional roles of Pin1.
Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/química , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Conformación Molecular , Simulación de Dinámica Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Relación Estructura-Actividad , Tiazolidinas/química , Tiazolidinas/metabolismoRESUMEN
PIN1 is considered as a therapeutic target for a wide variety of tumours. However, most of known inhibitors are devoid of cellular activity despite their good enzyme inhibitory profile. Hence, the lack of effective compounds for the clinic makes the identification of novel PIN1 inhibitors a hot topic in the medicinal chemistry field. In this work, we reported a virtual screening study for the identification of new promising PIN1 inhibitors. A receptor-based procedure was applied to screen different chemical databases of commercial compounds. Based on the whole workflow, two compounds were selected and biologically evaluated. Both ligands, compounds VS1 and VS2, showed a good enzyme inhibitory activity and VS2 also demonstrated a promising antitumoral activity in ovarian cancer cells. These results confirmed the reliability of our in silico protocol and provided a structurally novel ligand as a valuable starting point for the development of new PIN1 inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Relación Estructura-ActividadRESUMEN
The parvulin PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1), is the only enzyme capable of isomerizing prolines of phospho-Serine/Threonine-Proline motifs. PIN1 binds to a subset of proteins and plays an essential role in regulating protein function post-phosphorylation control. Furthermore, the activity of PIN1 regulates the outcome of the signalling of proline-directed kinases (e.g. MAPK, CDK, or GSK3) and thus regulates cell proliferation and cell survival. For these reasons, PIN1 inhibitors are interesting since they may have therapeutic implications for cancer. Several authors have already reported that the non-structural point mutation Trp34Ala prevents PIN1 from interacting with its downstream effector proteins. In this work, we characterized PIN1 structurally, intending to explore new inhibition targets for the rational design of pharmacological activity compounds. Through a conformational diversity analysis of PIN1, we identified and characterized a highly specific druggable pocket around the residue Trp34. This pocket was used in a high-throughput docking screening of 450,000 drug-like compounds, and the top 10 were selected for re-docking studies on the previously used conformers. Finally, we evaluated the binding of each compound by thermal shift assay and found four molecules with a high affinity for PIN1 and potential inhibitory activity. Through this strategy, we achieved novel drug candidates with the ability to interfere with the phosphorylation-dependent actions of PIN1 and with potential applications in the treatment of cancer.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Antineoplásicos , Inhibidores Enzimáticos , Peptidilprolil Isomerasa de Interacción con NIMA , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacología , Detección Precoz del Cáncer , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosforilación , Prolina/metabolismoRESUMEN
Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further in vivo experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Sistema de Administración de Fármacos con Nanopartículas/química , Tretinoina/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Quitosano/química , Modelos Animales de Enfermedad , Doxorrubicina/farmacocinética , Liberación de Fármacos , Sinergismo Farmacológico , Femenino , Ácido Fólico/química , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Micelas , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Distribución Tisular , Tretinoina/farmacocinéticaRESUMEN
Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors of aging and aging-related pathologies, including Alzheimer's disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.
Asunto(s)
Proteínas de Drosophila/metabolismo , Heterocromatina/metabolismo , Lamina Tipo B/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Estrés Mecánico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Células Cultivadas , Homólogo de la Proteína Chromobox 5/genética , Homólogo de la Proteína Chromobox 5/metabolismo , Elementos Transponibles de ADN/genética , Drosophila/metabolismo , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Humanos , Lamina Tipo B/química , Ratones , Ratones Endogámicos C57BL , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Neocórtex/citología , Neocórtex/metabolismo , Neuronas/citología , Neuronas/metabolismo , Membrana Nuclear/química , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Isomerasa de Peptidilprolil/genética , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño/metabolismoRESUMEN
BACKGROUND: Pin1, as the peptidyl-prolyl isomerase, plays a vital role in cellular processes. However, whether it has a regulatory effect on renal ischemia and reperfusion (I/R) injury still remains unknown. METHODS: The hypoxia/reoxygenation (H/R) model in human kidney (HK-2) cells and the I/R model in rats were assessed to investigate the role of Pin1 on I/R-induced acute kidney injury. Male Sprague-Dawley rats were used to establish the I/R model for 15, 30, and 45 min ischemia and then 24 h reperfusion, with or without the Pin1 inhibitor, to demonstrate the role of Pin1 in acute kidney injury. HK-2 cells were cultured and experienced the H/R model to identify the molecular mechanisms involved. RESULTS: In this study, we found that Pin1 and oxidative stress were obviously increased after renal I/R. Inhibition of Pin1 with juglone decreased renal structural and functional injuries, as well as oxidative stress. Besides, Pin1 inhibition with the inhibitor, juglone, or the small interfering RNA showed significant reduction on oxidative stress markers caused by the H/R process in vitro. Furthermore, the results indicated that the expression of p38 MAPK was increased during H/R in vitro and Pin1 inhibition could reduce the increased expression of p38 MAPK. CONCLUSION: Our results illustrated that Pin1 aggravated renal I/R injury via elevating oxidative stress through activation of the p38 MAPK pathway. These findings indicated that Pin1 might become the potential treatment for renal I/R injury.
Asunto(s)
Lesión Renal Aguda/metabolismo , Riñón/metabolismo , Sistema de Señalización de MAP Quinasas , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Estrés Oxidativo , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Animales , Línea Celular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Masculino , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Inflammatory bowel diseases (IBDs) are serious disorders of which the etiologies are not, as yet, fully understood. In this study, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) protein was shown to be dramatically upregulated in the colons of dextran sodium sulfate (DSS)-induced ulcerative colitis model mice. Interestingly, Pin1 knockout (KO) mice exhibited significant attenuation of DSS-induced colitis compared to wild-type (WT) mice, based on various parameters, including body weight, colon length, microscopic observation of the intestinal mucosa, inflammatory cytokine expression, and cleaved caspase-3. In addition, a role of Pin1 in inflammation was suggested because the percentage of M1-type macrophages in the colon was decreased in the Pin1 KO mice while that of M2-type macrophages was increased. Moreover, Pin1 KO mice showed downregulation of both Il17 and Il23a expression in the colon, both of which have been implicated in the development of colitis. Finally, oral administration of Pin1 inhibitor partially but significantly prevented DSS-induced colitis in mice, raising the possibility of Pin1 inhibitors serving as therapeutic agents for IBD.
Asunto(s)
Colitis/enzimología , Colon/enzimología , Mucosa Intestinal/enzimología , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Animales , Antiinflamatorios/farmacología , Colitis/inducido químicamente , Colitis/patología , Colitis/prevención & control , Colon/efectos de los fármacos , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Naftoquinonas/farmacologíaRESUMEN
The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , 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/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of the c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and therefore the key downstream effectors of this pathway, remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signaling in ICC that could open up therapeutic opportunities. APPROACH AND RESULTS: Using loss-of-function and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumors, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 through all-trans retinoic acid, a Food and Drug Administration-approved drug, impairs the growth of both cultured and xenografted ICC cells. CONCLUSIONS: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation through PIN1 inhibition.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/metabolismo , Carcinogénesis/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Animales , Antineoplásicos/administración & dosificación , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 9 Activada por Mitógenos/genética , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Fosforilación/efectos de los fármacos , Fosforilación/genética , ARN Interferente Pequeño/genética , Tretinoina/administración & dosificación , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in humans. The inhibition of peptidyl-prolyl cis/trans isomerase (Pin1) gene expression may have great potential in the treatment of HCC. N-Acetylgalactosamine (GalNAc) was used to target the liver. Cholesterol-modified antimicrobial peptide DP7 (DP7-C) acts as a carrier, the GalNAc-siRNA/DP7-C complex increases the uptake of GalNAc-siRNA and the escape of endosomes in hepatocytes. In addition, DP7-C nanoparticles and hydrogel-assisted GalNAc-Pin1 siRNA delivery can effectively enhance the stability and prolong the silencing effects of Pin1 siRNA. In an orthotopic liver cancer model, the GalNAc-Pin1 siRNA/DP7-C/hydrogel complex can potentially regulate Pin1 expression in hepatocellular carcinoma cells and effectively inhibit tumor progression. Our study proves that Pin1 siRNA is an efficient method for the treatment of HCC and provides a sustainable and effective drug delivery system for the suppression of liver cancer.
Asunto(s)
Acetilgalactosamina/química , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Animales , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada , Composición de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidrogeles/química , Inyecciones Subcutáneas , Neoplasias Hepáticas/genética , Ratones , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Proteínas Citotóxicas Formadoras de Poros/química , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , Termodinámica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Naftoquinonas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/efectos de los fármacos , Tretinoina/farmacología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Células PC-3 , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Dominios Proteicos , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pin1 is a peptidyl prolyl cis-trans isomerase (PPIase) and inhibiting Pin1 is a potential way for discovering anti-tumor agents. With an aim to find potent Pin1 inhibitors with a novel scaffold, a series of thiazole derivatives with an alicyclic heterocycles on the 2-position were designed, synthesized and tested against human Pin1. Compound 9p bearing a 2-oxa-6-azaspiro [3,3] heptane moiety on the thiazole scaffold was identified as the most potent Pin1 inhibitor of this series with an IC50 value of 0.95 µM. The structure-activity relationship (SAR) and molecular modeling study indicated that introducing an alicyclic ring with an H-bond acceptor would be a viable way to improve the binding affinity.
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Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Tiazoles/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaAsunto(s)
Cisteína , Inhibidores Enzimáticos/química , Peptidilprolil Isomerasa de Interacción con NIMA , Cisteína/química , Cisteína/metabolismo , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/química , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismoRESUMEN
Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.
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Antineoplásicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Animales , Antineoplásicos/química , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Cristalografía por Rayos X , Cisteína/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Ratones , Células 3T3 NIH , Peptidilprolil Isomerasa de Interacción con NIMA/química , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Conformación Proteica , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
New series of benzimidazole ring core conjugated with either dithiocarbamate or thiopropyl linkers, hybridized with different secondary amines were synthesized; 5-15 and 22-31; respectively. The new compounds were characterized by different spectroscopic techniques (1H, 13C 1D & 2D NMR, ESI-MS and IR). They were screened for in vitro anticancer activity against breast cancer using MCF7 cell line. The results obtained revealed that compounds 5, 12, 15 and 25 were the most active among the synthesized series exhibiting IC50 < 10 µg/ml against DOX. To characterize targeting breast cancer on molecular level, binding to 15N-labeled Pin1 enzyme was conducted using state-of-the-art 2D NMR binding experiments. Results showed promising binding between compounds 5, 12, and 25 by chemical shift perturbation (peak shifting or peak disappearance). Molecular docking study were quite valuable to explain the binding mode of active derivatives via hydrogen bonding. Additional contact preferences and surface mapping studies stated the similarity pattern between active candidates which may pave the way for more precise anti breast cancer target optimization.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Células MCF-7 , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Relación Estructura-ActividadRESUMEN
Gastric cancer is the third leading cause of cancer-related death worldwide. Diffuse type gastric cancer has the worst prognosis due to notorious resistance to chemotherapy and enrichment of cancer stem-like cells (CSC) associated with the epithelial-to-mesenchymal transition (EMT). The unique proline isomerase PIN1 is a common regulator of oncogenic signaling networks and is important for gastric cancer development. However, little is known about its roles in CSCs and drug resistance in gastric cancer. In this article, we demonstrate that PIN1 overexpression is closely correlated with advanced tumor stages, poor chemo-response and shorter recurrence-free survival in diffuse type gastric cancer in human patients. Furthermore, shRNA-mediated genetic or all-trans retinoic acid-mediated pharmaceutical inhibition of PIN1 in multiple human gastric cancer cells potently suppresses the EMT, cell migration and invasion, and lung metastasis. Moreover, PIN1 genetic or pharmaceutical inhibition potently eliminates gastric CSCs and suppresses their self-renewal and tumorigenicity in vitro and in vivo Consistent with these phenotypes, are that PIN1 biochemically targets multiple signaling molecules and biomarkers in EMT and CSCs and that genetic and pharmaceutical PIN1 inhibition functionally and drastically enhances the sensitivity of gastric cancer to multiple chemotherapy drugs in vitro and in vivo These results demonstrate that PIN1 inhibition sensitizes chemotherapy in gastric cancer cells by targeting CSCs, and suggest that PIN1 inhibitors may be used to overcome drug resistance in gastric cancer.
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Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Tretinoina/farmacología , Adulto , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , ARN Interferente Pequeño/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pin1 is one member of a group consisting of three prolyl isomerases. Pin1 interacts with the motif containing phospho-Ser/Thr-Pro of substrates and enhances cis-trans isomerization of peptide bonds, thereby controlling the functions of these substrates. Importantly, the Pin1 expression level is highly upregulated in most cancer cells and correlates with malignant properties, and thereby with poor outcomes. In addition, Pin1 was revealed to promote the functions of multiple oncogenes and to abrogate tumor suppressors. Accordingly, Pin1 is well recognized as a master regulator of malignant processes. Recent studies have shown that Pin1 also binds to a variety of metabolic regulators, such as AMP-activated protein kinase, acetyl CoA carboxylase and pyruvate kinase2, indicating Pin1 to have major impacts on lipid and glucose metabolism in cancer cells. In this review, we focus on the roles of Pin1 in metabolic reprogramming, such as "Warburg effects", of cancer cells. Our aim is to introduce these important roles of Pin1, as well as to present evidence supporting the possibility of Pin1 inhibition as a novel anti-cancer strategy.