RESUMEN
The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 µM, GIC50 = 8-10 µM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Naftoles/metabolismo , Naftoles/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Transporte de Electrón , Antituberculosos/metabolismoRESUMEN
Signal Transducer and Activator of Transcription (STAT) 3 emerged rapidly as a high-value target for treatment of cancer. However, small-molecule STAT3 inhibitors have been slow to enter the clinic due, in part, to serious adverse events (SAE), including lactic acidosis and peripheral neuropathy, which have been attributed to inhibition of STAT3's mitochondrial function. Our group developed TTI-101, a competitive inhibitor of STAT3 that targets the receptor pY705-peptide binding site within the Src homology 2 (SH2) domain to block its recruitment and activation. TTI-101 has shown target engagement, no toxicity, and evidence of clinical benefit in a Phase I study in patients with solid tumors. Here we report that TTI-101 did not affect mitochondrial function, nor did it cause STAT3 aggregation, chemically modify STAT3 or cause neuropathic pain. Instead, TTI-101 unexpectedly suppressed neuropathic pain induced by chemotherapy or in a spared nerve injury model. Thus, in addition to its direct anti-tumor effect, TTI-101 may be of benefit when administered to cancer patients at risk of developing chemotherapy-induced peripheral neuropathy (CIPN).
Asunto(s)
Hiperalgesia/tratamiento farmacológico , Naftoles/uso terapéutico , Neuralgia/tratamiento farmacológico , Fosforilación Oxidativa/efectos de los fármacos , Factor de Transcripción STAT3/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Tacto , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Hiperalgesia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Naftoles/farmacología , Neuralgia/metabolismo , Factor de Transcripción STAT3/metabolismo , Sulfonamidas/farmacologíaRESUMEN
Worldwide prevalence of esophageal adenocarcinomas with high rates of mortality coupled with increased mutations in esophageal cells warrants investigation to understand deregulation of cell signaling pathways leading to cancer. To this end, the current study was undertaken to unravel the cell death signatures using the model human esophageal adenocarcinoma cell line-OE33. The strategy involved targeting the key epigenetic modulator SIRT1, a histone deacetylase by a small molecule inhibitor - sirtinol. Sirtinol induced a dose-dependent inhibition of cell viability under both normoxic and hypoxic conditions with long term impact on proliferation as shown by clonogenic assays. Signature apoptotic signaling pathways including caspase activation and decreased Bcl-2 were observed. Proteomic analysis highlighted an array of entities affected including molecules involved in replication, transcription, protein synthesis, cell division control, stress-related proteins, spliceosome components, protein processing and cell detoxification/degradation systems. Importantly, the stoichiometry of the fold changes of the affected proteins per se could govern the cell death phenotype by sirtinol. Sirtinol could also potentially curb resistant and recurrent tumors that reside in hypoxic environments. Overall, in addition to unraveling the cellular, molecular and proteomics basis of SIRT1 inhibition, the findings open up avenues for designing novel strategies against esophageal adenocarcinoma.
Asunto(s)
Adenocarcinoma/genética , Benzamidas/farmacología , Neoplasias Esofágicas/genética , Naftoles/farmacología , Sirtuina 1/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Benzamidas/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Ensayos de Selección de Medicamentos Antitumorales , Epigénesis Genética/efectos de los fármacos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Naftoles/uso terapéutico , Proteómica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sirtuina 1/metabolismoRESUMEN
Metastatic prostate cancer (PCa) has high mortality and a poor 5-year survival rate primarily due to the lack of effective treatments. Bone is the primary site of PCa metastasis in humans and the development of reliable therapeutic options for bone metastatic PCa will make a huge impact in reducing the mortality among these patients. Although P21 activated kinases (PAKs) have been studied in the past for their role in cancer, the efficacy of targeting PAKs to treat lung and bone metastatic PCa has not been tested yet. In the current study, we report that targeting PAK1 using IPA-3, an allosteric inhibitor of PAK1 kinase activity, significantly inhibits the murine metastatic PCa (RM1) cell proliferation and motility in vitro, and metastasis to the lungs in vivo. More importantly, we demonstrate for the first time that treatment with IPA-3 can blunt metastatic PCa-induced bone remodeling in vivo as analyzed by the 3-dimensional microcomputer tomography analysis. Our study has identified IPA-3 as a potential drug to treat bone metastatic PCa.
Asunto(s)
Remodelación Ósea/efectos de los fármacos , Disulfuros/farmacología , Disulfuros/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Naftoles/farmacología , Naftoles/uso terapéutico , Neoplasias de la Próstata/patología , Quinasas p21 Activadas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Tibia/patologíaRESUMEN
Noise is one of the most common causes of hearing loss in industrial countries. There are many studies about chemical agents to prevent noise-induced hearing loss (NIHL). However, there is no commercially available drug yet. Retinoic acid is an active metabolite of Vitamin A; it has an anti-apoptic role in NIHL. This study aims to verify the differences among selective agonists of retinoic acid receptors (RARs) in NIHL. All-trans retinoic acid (ATRA), AM80 (selective retinoic acid receptor α agonist), AC261066 (Selective retinoic acid receptor ß1 agonist), and CD1530 (Selective retinoic acid λ agonist) were injected to 6-7 weeks old CJ5BL/6 mice before noise (110 dB for 3 h) exposure. In the auditory brainstem response test pre-, post 1, 3, and 7 days after noise exposure, not only ATRA but all kinds of selective RAR agonists showed protective effects in hearing threshold and wave I amplitude. Though there was no significant difference in the level of protective effects between agonists, α agonist showed the most prominent effect in preserving hearing function as well as outer hair cells after noise exposure. In conclusion, selective agonists of RAR demonstrate comparable protective effects against NIHL to retinoic acid. Given that these selective RAR agonists have less side effects than retinoic acid, they may be promising potential drugs against NIHL.
Asunto(s)
Benzoatos/uso terapéutico , Pérdida Auditiva Provocada por Ruido/prevención & control , Naftoles/uso terapéutico , Receptores de Ácido Retinoico/agonistas , Tetrahidronaftalenos/uso terapéutico , Tiazoles/uso terapéutico , Tretinoina/uso terapéutico , Animales , Ratones Endogámicos C57BL , Ruido/efectos adversosRESUMEN
BACKGROUND: p21-activated kinase 1 (PAK1) plays a fundamental role in promoting the development and progression of several cancers and is a potential therapeutic target. However, the biological function and underlying mechanism of PAK1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: The expression of PAK1 was detected in both ESCC cell lines and clinical samples. Cell growth was measured by MTT, focus formation and soft agar assays. Cell migration and invasion were detected by wound healing and transwell assays. Animal models of subcutaneous tumourigenicity and tail vein metastasis were performed to determine the inhibitory effect of pharmacological inhibitor IPA-3 on tumor growth and metastasis of ESCC cells. RESULTS: We found that PAK1 was frequently overexpressed in ESCC. Ectopic expression of PAK1 promoted cellular growth, colony formation and anchorage-independent growth. Overexpressing PAK1 also enhanced migration, invasion and the expression of MMP-2 and MMP-9 in ESCC cells. In contrast, silencing PAK1 by lentiviral knockdown or a specific inhibitor IPA-3 resulted in a contrary effect. Subsequent investigations revealed that Raf1/MEK1/ERK signaling pathway was involved in PAK1-mediated effect. Enhanced expression of Raf1 attenuated the inhibitory functions of PAK1 shRNA. Whereas blocking of Raf1 by shRNA or specific inhibition of MEK1 by U0126 antagonized the oncogenetic effect of PAK1 on ESCC cells. More importantly, Pharmacological inhibition of PAK1 by IPA-3 significantly suppressed tumor growth and lung metastasis of ESCC cells in vivo. CONCLUSIONS: These data support that PAK1 is an ideal target for the development of potential therapeutic drugs for ESCC patients even with metastasis.
Asunto(s)
Disulfuros/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Naftoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinasas p21 Activadas/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Animales , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Disulfuros/uso terapéutico , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/secundario , Humanos , MAP Quinasa Quinasa 1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos BALB C , Persona de Mediana Edad , Naftoles/uso terapéutico , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Dendritic cell (DC) trafficking from lung to the draining mediastinal lymph nodes (MLNs) is a key step for initiation of T cell responses in allergic asthma. In the present study, we investigate the role of DC-mediated airway inflammation after inhibition of p21-activated kinase-1 (PAK1), an effector of Rac and Cdc42 small GTPases, in the allergen-induced mouse models of asthma. Systemic administration of PAK1 specific inhibitor IPA-3 significantly attenuates not only the airway inflammation but also the airway hyperresponsiveness in a mouse model of ovalbumin-induced asthma. Specifically, intratracheal administration of low dosage of IPA-3 consistently decreases not only the airway inflammation but also the DC trafficking from lung to the MLNs. Importantly, intratracheal instillation of IPA-3-treated and ovalbumin-pulsed DCs behaves largely the same as that of either Rac inhibitor-treated and ovalbumin-pulsed DCs or Cdc42 inhibitor-treated and ovalbumin-pulsed DCs in attenuation of the airway inflammation in ovalbumin-challenged mice. Mechanistically, PAK1 is not involved in the maturation, apoptosis, antigen uptake, and T cell activation of cultured DCs, but PAK1 dose lie on the downstream of Rac and Cdc42 to regulate the DC migration toward the chemokine C-C motif chemokine ligand 19. Taken together, this study demonstrates that inhibition of PAK1 attenuates the cardinal features of asthma through suppressing the DC trafficking from lung to the MLN, and that interfere with DC trafficking by a PAK1 inhibitor thus holds great promise for the therapeutic intervention of allergic diseases.
Asunto(s)
Asma/metabolismo , Células Dendríticas/metabolismo , Ganglios Linfáticos/metabolismo , Quinasas p21 Activadas/antagonistas & inhibidores , Quinasas p21 Activadas/metabolismo , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Broncoconstrictores/toxicidad , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Disulfuros/farmacología , Disulfuros/uso terapéutico , Relación Dosis-Respuesta a Droga , Ganglios Linfáticos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Naftoles/farmacología , Naftoles/uso terapéutico , Ovalbúmina/toxicidadRESUMEN
A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
Asunto(s)
Antibacterianos/clasificación , Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Retinoides/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Animales , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Benzoatos/química , Benzoatos/farmacología , Benzoatos/uso terapéutico , Benzoatos/toxicidad , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/microbiología , Muerte Celular/efectos de los fármacos , Línea Celular , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Gentamicinas/farmacología , Gentamicinas/uso terapéutico , Humanos , Membrana Dobles de Lípidos/química , Staphylococcus aureus Resistente a Meticilina/citología , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Ratones , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Mutación , Naftoles/química , Naftoles/farmacología , Naftoles/uso terapéutico , Naftoles/toxicidad , Retinoides/química , Retinoides/uso terapéutico , Retinoides/toxicidadRESUMEN
MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and γ-secretase inhibitor (γSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that γSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and γSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation.
Asunto(s)
MicroARNs/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Benzamidas/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Naftoles/uso terapéutico , Ácido Zoledrónico/uso terapéuticoRESUMEN
G protein-coupled receptor 35 (GPR35), a receptor for lysophosphatidic acid, is highly expressed in the gastrointestinal tract. Recently, GPR35 has been implicated in the onset of inflammatory bowel disease (IBD), but its role in physiological and pathological processes in the colon remains undefined. In this study, we investigated the contribution of GPR35-mediated signalling to mucosal repair of colonic epithelium in IBD. GPR35 function was examined in a wound healing model, using young adult mouse colon epithelium (YAMC) cells, and in a dextran sulphate sodium (DSS)-induced mouse model of colitis. Cell proliferation, mRNA expression, extracellular signal-regulated kinase (ERK) activation, and protein localization were determined by MTT assay, quantitative RT-PCR, western blotting, and immunohistochemistry, respectively. GPR35 agonists (YE120, zaprinast, and pamoic acid) promoted wound repair in a concentration-dependent manner independently of cell proliferation, whereas a specific GPR35 antagonist CID2745687, forskolin, and pertussis toxin reversed the YE120-induced effect. YE120 increased the mRNA expression of fibronectin and its receptor integrin α5, and ERK1/2 phosphorylation, but these responses were attenuated by CID2745687 and forskolin. Furthermore, the severity of DSS-induced colitis was significantly reduced by daily injections of pamoic acid via upregulation of fibronectin and integrin α5 in the colonic epithelium. GPR35 signalling promotes mucosal repair by inducing fibronectin and integrin α5 expression, coupling to Gi protein, and activating ERK1/2 in colonic epithelial cells. These findings define GPR35 as a candidate therapeutic target in IBD.
Asunto(s)
Movimiento Celular/fisiología , Colon/citología , Células Epiteliales/fisiología , Mucosa Intestinal/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Cicatrización de Heridas/fisiología , Animales , Línea Celular , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/patología , Colon/metabolismo , Colon/patología , Citocinas/genética , Sulfato de Dextran , Células Epiteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibronectinas/metabolismo , Furanos/farmacología , Integrinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Naftoles/uso terapéutico , Nitrilos/farmacología , Peroxidasa/metabolismo , Purinonas/farmacología , ARN Mensajero/metabolismo , Ratas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
STUDY DESIGN: Ninety-six male adult CD-1 mice were randomly divided into sham, spinal cord injury (SCI)â+âvehicle, and SCIâ+âIPA-3 groups. Expression of matrix metalloproteinase (MMP)-2 and MMP-9, production of tumor necrosis factors (TNF)-α and interleukin (IL)-1ß, tissue edema, blood-spinal cord barrier penetrability, neural cell apoptosis, and neurological function recovery were measured. OBJECTIVE: The aim of the study was to evaluate the effect of specific inhibition of p21-activated kinase 1 (PAK1) by IPA-3 on SCI and the underlying mechanisms thereof. SUMMARY OF BACKGROUND DATA: SCI is a devastating clinical condition that may result in long-lasting and deteriorating functional deficits. The major goal of SCI treatment is to limit the development of secondary injury. IPA-3, a PAK1 inhibitor, exhibited neuroprotection against secondary damage after traumatic brain injury and subarachnoid hemorrhage (SAH). METHODS: MMP-2, MMP-9, and cleaved caspase-3 expression were assessed by Western blot. Inflammatory cytokines TNF-α and IL-1ß were detected by enzyme-linked immunosorbent assay (ELISA). The blood-spinal cord barrier disruption was measured by water content and Evans blue extravasation of the spinal cord. Neuronal apoptosis was evaluated by Nissl staining and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay. The locomotor behavior of hind limb was evaluated by Basso Mouse Scale (BMS) at 1, 3, 7, 14, and 28 days post-injury. RESULTS: Compared with SCIâ+âvehicle mice, IPA-3 treatment showed decreased p-PAK1, MMP-2, MMP-9, cleaved caspase-3, TNF-α, and IL-1ß expression. Moreover, inhibition of PAK1 by IPA-3 reduced spinal cord water content and Evans blue extravasation, increased neuronal survival, and reduced TUNEL-positive cells at 24 hours after SCI. Furthermore, IPA-3 improved spinal cord functional recovery 7 days after SCI. CONCLUSION: Inhibition of PAK1 by IPA-3 promoted recovery of neurological function, possibly by downregulating the expression of MMP-2, MMP-9, TNF-α, and IL-1ß. Our data suggest that PAK1 may be a potential therapeutic target in patients with SCI. LEVEL OF EVIDENCE: 1.
Asunto(s)
Disulfuros/uso terapéutico , Actividad Motora/efectos de los fármacos , Naftoles/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Quinasas p21 Activadas/antagonistas & inhibidores , Animales , Disulfuros/farmacología , Masculino , Ratones , Actividad Motora/fisiología , Naftoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Distribución Aleatoria , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/enzimología , Traumatismos de la Médula Espinal/fisiopatología , Quinasas p21 Activadas/metabolismoRESUMEN
Two new naphthalenone compounds were isolated from green walnut husks of Juglans mandshurica and their structures were identified as 4-butoxybutoxy-5,8-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (1), 4-ethoxyethoxy-5,8-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (2). Compounds 1 and 2 were named as Juglanstetralone A (1) and Juglanstetralone B (2). Compound 1 showed more significant anti-tumor activity than 2 against gastric cancer BGC-823 cells, wih the IC50 of 125.89 (g(mL(-1).
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Juglans/química , Naftoles/uso terapéutico , Nueces/química , Neoplasias Gástricas/tratamiento farmacológico , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Humanos , Naftoles/aislamiento & purificación , Naftoles/farmacología , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Melanoma continues to cause more deaths than any other skin cancer, necessitating the development of new avenues of treatment. One promising new opportunity comes in the form of mechanism-based therapeutic targets. We recently reported the overexpression and delocalization of the class III histone deacetylase SIRT1 in melanoma, and demonstrated that its small molecule inhibition via Tenovin-1 decreased cell growth and viability of melanoma cells, possibly by a p53 mediated induction of p21. Here, we support our data using additional SIRT inhibitors, viz. Sirtinol and Ex-527, which suggests possible benefits of concomitantly inhibiting more than one Sirtuin for an effective cancer management strategy. This "Extra View" paper also includes a discussion of our results in the context of similar recent and concurrent studies. Furthermore, we expand upon our findings in an analysis of new research that may link the cellular localization and growth effects of SIRT1 with the PI3K signaling pathway.
Asunto(s)
Benzamidas/uso terapéutico , Carbazoles/uso terapéutico , Histona Desacetilasas del Grupo III/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Terapia Molecular Dirigida , Naftoles/uso terapéutico , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Carbazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Clonales , Humanos , Melanoma/patología , Modelos Biológicos , Naftoles/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Sirtuins are a class of enzymes with nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylase function. By deacylating various substrate proteins, including histones, transcription factors, and metabolic enzymes, sirtuins regulate various biological processes, such as transcription, cell survival, DNA damage and repair, and longevity. Small molecules that can inhibit sirtuins have been developed and many of them have shown anticancer activity. Here, we summarize the major biological findings that connect sirtuins to cancer and the different types of sirtuin inhibitors developed. Interestingly, biological data suggest that sirtuins have both tumor-suppressing and tumor-promoting roles. However, most pharmacological studies with small-molecule inhibitors suggest that inhibiting sirtuins has anticancer effects. We discuss possible explanations for this discrepancy and suggest possible future directions to further establish sirtuin inhibitors as anticancer agents.
Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/química , Sirtuinas/antagonistas & inhibidores , Animales , Antineoplásicos/metabolismo , Antineoplásicos/uso terapéutico , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/uso terapéutico , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Humanos , Naftoles/química , Naftoles/metabolismo , Naftoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Niacinamida/uso terapéutico , Unión Proteica , Especies Reactivas de Oxígeno/metabolismo , Sirtuinas/metabolismoRESUMEN
Numerous derivatives of kojic acid have been synthesised to expand its immunopharmacological uses. Kojic acid is known to have anti-cancer, anti-inflammatory, and anti-melanogenesis effects. We found that (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl 6-hydroxynaphthalene-2-carboxylate (MHNC) strongly suppressed the production of nitric oxide (NO) in an initial screening experiment. In this study, we explored the in vitro and in vivo anti-inflammatory activity of MHNC and its inhibitory mechanisms using lipopolysaccharide (LPS)-treated RAW264.7 cells and HCl/EtOH-treated ICR mice. MHNC dose-dependently diminished the secretion of nitric oxide (NO) and prostaglandin (PG)E2 in LPS-treated RAW264.7 cells. This compound also suppressed the upregulation of mRNA levels for the inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 genes. Additionally, the transcriptional activation of these genes was inhibited by MHNC through the suppression of the nuclear translocation of nuclear factor (NF)-κB subunits (p65 and p50), as determined by a luciferase reporter assay. Interestingly, MHNC treatment was found to suppress a series of upstream signalling cascades consisting of IκBα, AKT, PDK1, Src, and Syk for NF-κB activation. Furthermore, a direct enzyme assay with purified Src and Syk and luciferase assays using Src and Syk overexpression indicated that these enzymes were directly inhibited by MHNC. Finally, MHNC (20mg/kg) prevented inflammatory symptoms of the stomach in mice treated with HCl/EtOH by reducing phospho-IκBα levels. Taken together, our data suggest that MHNC may negatively modulate in vitro and in vivo inflammatory responses via the direct suppression of Syk/Src and NF-κB.
Asunto(s)
Antiinflamatorios/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Naftoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pironas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Antiinflamatorios/uso terapéutico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Dinoprostona/metabolismo , Etanol , Gastritis/inducido químicamente , Gastritis/tratamiento farmacológico , Gastritis/inmunología , Gastritis/patología , Células HEK293 , Humanos , Ácido Clorhídrico , Proteínas I-kappa B/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Masculino , Ratones Endogámicos ICR , Inhibidor NF-kappaB alfa , FN-kappa B/inmunología , Naftoles/uso terapéutico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Proteínas Tirosina Quinasas/inmunología , Pironas/química , Pironas/uso terapéutico , Estómago/efectos de los fármacos , Estómago/inmunología , Estómago/patología , Quinasa Syk , Familia-src Quinasas/inmunologíaRESUMEN
Two new 7,6'-coupled naphthylisoquinolines, namely ancistrotectorines A (1) and B (2), two new 5,3'-coupled naphthylisoquinolines, namely ancistrotectorines C (3) and D (4), and one new 7,8-coupled naphthylisoquinoline, namely ancistrotectorine E (5), together with 9 known naphthylisoquinoline alkaloids, hamatine (6), ancistrobertsonine B (7), ancistrocladinine (8), hamatinine (9), ancistrotanzanine A (10), ancistrotanzanine B (11), ancistrotectoriline B (12), 7-epi-ancistrobrevine D (13), and ancistrotectorine (14), were isolated from the 70% EtOH extract of Ancistrocladus tectorius. Their structures were elucidated based on the extensive analysis of spectroscopic data (1D, 2D NMR and MS). Compound 5 exhibited inhibitory activities against HL-60, K562 and U937 cell lines with IC50 values of 1.70, 4.18 and 2.56 µM respectively.
Asunto(s)
Isoquinolinas/aislamiento & purificación , Leucemia/tratamiento farmacológico , Magnoliopsida/química , Naftoles/uso terapéutico , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Células HL-60 , Humanos , Concentración 50 Inhibidora , Isoquinolinas/química , Isoquinolinas/farmacología , Células K562 , Estructura Molecular , Naftoles/química , Naftoles/aislamiento & purificación , Naftoles/farmacología , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Tallos de la Planta/química , Células U937RESUMEN
Resveratrol is known to exert a cardioprotective effect against hypoxia/reoxygenation (H/R) injury. HS-1793 is a novel, more stable resveratrol analog, but its cardioprotective effects were unknown. The present study aimed to test the cardioprotective effect of HS-1793 against H/R injury and investigate the role of mitochondria in Sprague Dawley rat heart damage using an ex vivo Langendorff system. HS-1793 ameliorated H/R-induced mitochondrial dysfunction by reducing mitochondrial reactive oxygen species production, improving mitochondrial oxygen consumption and suppressing mitochondrial calcium (Ca(2+)) overload during reperfusion. Moreover, HS-1793-treated rat heart showed reduced infarct size. Our data suggest that HS-1793 can protect cardiac against mitochondrial damage following H/R, thereby suppressing injury.
Asunto(s)
Naftoles/química , Resorcinoles/química , Estilbenos/química , Animales , Calcio/metabolismo , Corazón/fisiopatología , Hipoxia , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Naftoles/farmacología , Naftoles/uso terapéutico , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Resorcinoles/farmacología , Resorcinoles/uso terapéutico , ResveratrolRESUMEN
Natural agents with the immunomodulating property have been gaining traction to be employed in the complementary therapy of cancer because the ineffectiveness of numerous therapeutic strategies may be related in part to the tumor-induced immunosuppressive phenotypes, especially regulatory T (Treg) cells found in the tumor microenvironment. The present study was undertaken to examine whether HS-1793, synthetic resvertrol analog free from the restriction of metabolic instability and high dose requirement of resveratrol, induces an in vivo anti-tumor effect in FM3A tumor bearing mice through the suppression of Treg cells, which contribute to an increase in tumor specific cytotoxic T cell responses. Intraperitoneal injections of HS-1793 showed not only therapeutic benefits on established tumors, but also preventive anti-tumor effects. Treg cells (CD4+CD25+Foxp3+ cells) were significantly reduced in the total splenocytes as well as tumor tissues from HS-1793-administered mice, and the production of TGF-ß inducing Treg showed a similar pattern. On the contrary, the administration of HS-1793 increased IFN-γ-expressing CD8+ T cells, upregulated IFN-γ production, and enhanced the cytotoxicity of splenocytes against FM3A tumor cells both in therapeutic and preventive experimental animals. These results demonstrated the suppressive role of HS-1793 on the function of Treg cells contributing to tumor specific cytotoxic T lymphocyte responses in tumor-bearing mice, which explained the underlying mechanism of the anti-tumor immunity of HS-1793.
Asunto(s)
Antineoplásicos/farmacología , Naftoles/farmacología , Neoplasias/inmunología , Resorcinoles/farmacología , Linfocitos T/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C3H , Naftoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Resorcinoles/uso terapéutico , Bazo/citología , Bazo/inmunología , Linfocitos T/inmunología , Carga Tumoral/efectos de los fármacosRESUMEN
Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex(®) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.
Asunto(s)
Antioxidantes/química , Activadores de Enzimas/química , Inhibidores Enzimáticos/química , Naftoles/química , Sirtuinas/metabolismo , Estilbenos/química , Antioxidantes/uso terapéutico , Activadores de Enzimas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/enzimología , VIH/efectos de los fármacos , VIH/fisiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/enzimología , Humanos , Naftoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/enzimología , Obesidad/tratamiento farmacológico , Obesidad/enzimología , Sirtuinas/antagonistas & inhibidores , Estilbenos/uso terapéutico , Relación Estructura-ActividadRESUMEN
OBJECTIVE: In our previous study, we had isolated a series of lignan compounds, termed vitexins, from the seed of Chinese herb Vitex negundo and found broad antitumor activities of these compounds in many cancer xenograft models and cell lines. This study was aimed to determine the antitumor effect of purified vitexin compound 1 (VB1) on choriocarcinoma in vitro and in vivo. MATERIALS AND METHODS: The severe combined immunodeficiency mouse model of choriocarcinoma was established to investigate the in vivo effect of VB1. Its effect on proliferation and apoptosis in JEG-3 cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay and flow cytometry, respectively. The expression of caspase-3, Bcl-2, and some molecules involved in the mammalian target of rapamycin (mTOR) signaling was detected by Western blot. RESULTS: Vitexin compound 1 significantly inhibited the growth of choriocarcinoma in severe combined immunodeficient mice and reduced the serum ß-human chorionic gonadotropin level. Vitexin compound 1 inhibited cell proliferation, induced apoptosis, and inhibited the mTOR signaling in JEG-3 cell line. CONCLUSION: Vitexin compound 1 could inhibit choriocarcinoma via inducing cell apoptosis and suppressing the mTOR pathway.