RESUMO
Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.
Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Neoplasias Pancreáticas , Humanos , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin (3f) was the most promising compound with a PC50 value of 0.11 µM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f, demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.
Assuntos
Antineoplásicos Fitogênicos , Naftoquinonas , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Fosfatidilinositol 3-Quinases , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Pancreatic cancer is one of the deadliest types of malignancies. A new intervention aiming to combat pancreatic cancer is targeting its extra-ordinary ability to tolerate nutrition starvation, a phenomenon known as "Austerity". As a part of a research program aiming to develop a new-generation of anticancer agents, known as "anti-austerity agents", guggulsterone derivatives (GSDs) were identified as unique anti-austerity agents in terms of potency and selectivity. These agents are able to exert preferential cytotoxic activity only under nutrient-deprived conditions with little or no toxicity under normal conditions. In the present study, a library of 14 GSDs was synthesized and screened against PANC-1 human pancreatic cells. Among tested compounds, GSD-11 showed the most potent activity with PC50 a value of 0.72 µM. It also inhibited pancreatic cancer cell migration and colony formation in a concentration-dependent manner. A mechanistic study revealed that this compound can inhibit the activation of the Akt/mTOR signaling pathway. Therefore, GSD-11 could be a promising lead compound for the anticancer drug discovery against pancreatic cancer.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Pancreáticas/tratamento farmacológico , Pregnenodionas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pregnenodionas/síntese química , Pregnenodionas/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais CultivadasRESUMO
From the methanolic extract of the rhizomes of Boesenbergia pandurata, a new flavanone derivative named (2R,7â³S)-8-(1-phenyl-2-carboxyethyl)pinocembrin (1) and four known flavonoids (2-5) were isolated. Its absolute configuration was concluded by NMR and MS spectroscopic analysis, together with comparison between experimental and calculated ECD data. In turn, compound 1 exhibited strong cytotoxicity against the PANC-1 human pancreatic cancer cell line with a PC50 value of 6.4 µM under nutrient-deprived conditions, comparable with that of arctigenin (PC50, 0.83 µM).
Assuntos
Antineoplásicos Fitogênicos , Flavanonas , Zingiberaceae , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Flavanonas/análise , Flavanonas/farmacologia , Humanos , Rizoma/química , Zingiberaceae/químicaRESUMO
Pancreatic tumors are hypovascular, which leads to a poor nutrient supply to support the aggressively proliferating tumor cells. However, human pancreatic cancer cells have extreme resistance to nutrition starvation, which enables them to survive under severe metabolic stress conditions within the tumor microenvironment, a phenomenon known as "austerity" in cancer biology. Discovering agents which can preferentially inhibit the cancer cells' ability to tolerate starvation conditions represents a new generation of anticancer agents. In this study, geranyl 2,4-dihydroxy-6-phenethylbenzoate (GDP), isolated from Boesenbergia pandurata rhizomes, exhibited potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition starvation conditions. GDP also possessed PANC-1 cell migration and colony formation inhibitory activities under normal nutrient-rich conditions. Mechanistically, GDP inhibited PI3K/Akt/mTOR/autophagy survival signaling pathway, leading to selective PANC-1 cancer cell death under the nutrition starvation condition. Therefore, GDP is a promising anti-austerity agent for drug development against pancreatic cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
PPARα is a ligand-dependent transcription factor and its activation is known to play an important role in cell defense through anti-inflammatory and antioxidant effects. MHY3200 (2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2,2-difluoroacetic acid), a novel benzothiazole-derived peroxisome proliferator-activated receptor α (PPARα) agonist, is a synthesized PPARα activator. This study examined the beneficial effects of MHY3200 on age-associated alterations in reactive oxygen species (ROS)/Akt/forkhead box (FoxO) 1 signaling in rat kidneys. Young (7-month-old) and old (22-month-old) rats were treated with MHY3200 (1 mg/kg body weight/day or 3 mg/kg body weight/day) for two weeks. MHY3200 treatment led to a notable decrease in triglyceride and insulin levels in serum from old rats. The elevated kidney ROS level, serum insulin level, and Akt phosphorylation in old rats were reduced following MHY3200 treatment; moreover, FoxO1 phosphorylation increased. MHY3200 treatment led to the increased level of FoxO1 and its target gene, MnSOD. MHY3200 suppressed cyclooxygenase-2 expression by activating PPARα and inhibiting the activation of nuclear factor-κB (NF-κB) in the kidneys of old rats. Our results suggest that MHY3200 ameliorates age-associated renal inflammation by regulating NF-κB and FoxO1 via ROS/Akt signaling.
Assuntos
Acetatos/farmacologia , Envelhecimento/efeitos dos fármacos , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , PPAR alfa/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tiazóis/farmacologia , Acetatos/uso terapêutico , Animais , Peso Corporal , Regulação da Expressão Gênica , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Rim/patologia , Masculino , PPAR alfa/metabolismo , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/uso terapêutico , Fatores de Tempo , Triglicerídeos/metabolismoRESUMO
Ethanolic extract of Nelumbo nucifera petals showed preferential cytotoxic activity against HeLa human cervical cancer cell line with a PC50 value of 10.4 µg/mL. This active extract was subjected to a phytochemical investigation study which led to the isolation of nine benzylisoquinoline alkaloids (1-9). The isolated compounds exhibited potent antiausterity activities. Moreover, under nutrient-deprived conditions, (-)-lirinidine (8) induced remarkable alterations in HeLa cell morphology including cell shrinkage and plasma blebbing leading to total cell death within 10 h. Mechanistically, 8 was found to inhibit Akt/mTOR signaling pathway. It also induced apoptosis by promoting caspase-3 activation and inhibiting Bcl-2 expression. Therefore, benzylisoquinoline alkaloids skeleton can be considered as a promising scaffold for the anticancer drug development against cervical cancer.
Assuntos
Alcaloides/farmacologia , Benzilisoquinolinas/farmacologia , Neoplasias do Colo do Útero/patologia , Feminino , Células HeLa , HumanosRESUMO
The antiausterity strategy is a promising approach for the discovery of lead compounds with unprecedented anticancer activities by targeting the tolerance of cancer cells to nutrition starvation. These agents are selectively cytotoxic under the tumor microenvironment-mimicking condition of nutrition starvation, without apparent toxicity in the normal nutrient-rich condition. In this study, an ethanol extract of Betula alnoides showed antiausterity activity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 13.2 µg/mL. Phytochemical investigation of this active extract led to the isolation of eight benzophenones (1-8), including six new compounds, named betuphenones A-F (2-7), and three known xanthones (9-11). The structure elucidation of the new compounds was achieved by HRFABMS, NMR, and ECD spectroscopic analyses. A plausible biogenetic pathway of the new compounds was proposed. Compounds 1-7 displayed antiausterity activity with PC50 values of 4.9-8.4 µM. Moreover, compounds 2 and 7 induced alterations in PANC-1 cell morphology under nutrient-deprived conditions and also inhibited PANC-1 colony formation under nutrient-rich conditions.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzofenonas/farmacologia , Betula/química , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofenonas/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Casca de Planta/química , Tailândia , Microambiente Tumoral/efeitos dos fármacosRESUMO
A methanolic extract of Thai Piper ribesoides showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition, with a PC50 value of 24 µg/mL. Phytochemical investigation of this bio-active extract led to the isolation of six compounds (1-6), including two new polyoxygenated cyclohexane derivatives, named ribesoidones A and B (1 and 2). The structural elucidation of the new compounds was achieved by a combination of HREIMS, NMR, and circular dichroism spectroscopic analyses. Isolated compounds were tested for their antiausterity activity against PANC-1 human pancreatic cancer cell line. Among these, compounds 1, 3, and 4 displayed potent preferential cytotoxic activity with PC50 values of 5.5-7.2 µM. Ribesoidone A (1) was also found to inhibit PANC-1 colony formation under normal nutrient-rich conditions.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Pancreáticas/patologia , Piper/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Caules de Planta/química , TailândiaRESUMO
An ethanolic extract of Derris scandens flowers showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived condition, with a PC50 value of 0.7 µg/mL. Phytochemical investigation of this active extract led to the isolation of four prenylated isoflavones (1-4) including a new compound named 4'-O-methylgrynullarin (1). The structure elucidation of the new compound was achieved by HRFABMS and NMR spectroscopic analysis. The isolated compounds exhibited potent anti-austerity activity against four different human pancreatic cancer cell lines under nutrient-deprived conditions. The new compound 4'-O-methylgrynullarin (1) was also found to inhibit PANC-1 cell migration and colony formation under nutrient-rich condition. Mechanistically, compound 1 inhibited key survival proteins in the Akt/mTOR signaling pathway. Therefore, 4'-O-methylgrynullarin (1) can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Morte Celular/efeitos dos fármacos , Hemiterpenos/farmacologia , Isoflavonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Derris/química , Ensaios de Seleção de Medicamentos Antitumorais , Flores/química , Hemiterpenos/síntese química , Hemiterpenos/isolamento & purificação , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Human pancreatic tumor cells have an intrinsic ability to tolerate nutrition starvation and survive in the hypovascular tumor microenvironment, the phenomenon termed as "austerity". Searching for an agent that inhibits such tolerance to nutrient starvation and kills the pancreatic cancer cells preferentially in nutrient-starvation is a unique anti-austerity strategy in anti-cancer drug discovery. In this strategy, plant extracts and compounds are tested against PANC-1 human pancreatic cancer cell line under the conditions of nutrient-deprived medium (NDM) and nutrient-rich medium (DMEM), to discover the compounds that show selective cytotoxicity in NDM. Screening of twenty-five Thai indigenous medicinal plant extracts for their anti-austerity activity against the PANC-1 human pancreatic cancer cell line in nutrient deprived medium (NDM) resulted in the identification of four active plants, Derris scandens, Boesenbergia pandurata, Citrus hystrix, and Kaempferia parviflora, with PC50 values 0.5-8.9 µg/mL. K. parviflora extract also inhibited PANC-1 cancer cell colony formation. Phytochemical investigation of K. parviflora extract led to the isolation of fourteen compounds, including two polyoxygenated cyclohexanes (1 and 2), eleven flavonoids (3-13), and ß-sitosterol (14). Stereochemical assignment of compound 1 was confirmed through X-ray analysis. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 cells. Among them, 5-hydroxy-7-methoxyflavone (3) displayed the most potent activity with a PC50 value of 0.8 µM. Mechanistically, it was found to induce apoptosis in PANC-1 cell death in NDM as evident by caspase cleavage. It was also found to inhibit PANC-1 cancer cell colony formation in DMEM. Therefore, compound 3 can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.
RESUMO
The 70% ethanolic extract of Artemisia vulgaris showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition with PC50 12.5 µg/mL. A phytochemical investigation of this extract yielded a new bicyclic [4:3:0] sesquiterpene named (+)-vulgaric acid (1), together with eight previously reported compounds. The structural elucidation of 1 was achieved by HRFABMS and NMR analysis. The absolute configuration of 1 was deduced by computational calculations of ECD data. All isolated compounds were tested for preferential cytotoxicity against PANC-1 cells, and apigenin (3) showed the strongest activity with PC50 30.7 µM.
Assuntos
Antineoplásicos Fitogênicos , Artemisia , Neoplasias Pancreáticas , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
A phytochemical investigation of an ethanolic extract of Anneslea fragrans twigs collected from Thailand resulted in the discovery of a new dihydrochalcone glucopyranoside named fragranone C (1), together with six previously reported compounds. The structural elucidation of the new compound was achieved by HRFABMS, NMR spectroscopic analysis and acid hydrolysis.[Figure: see text].
Assuntos
Chalconas , Ericales , Estrutura Molecular , Extratos Vegetais , TailândiaRESUMO
Age- or high fat diet (HFD)-associated renal structural changes are commonly associated with a decline in renal function. Although HFD causes injurious effects in various organs during aging, its effects on age-associated renal fibrosis have not yet been investigated. In this study, we show that a short-term HFD significantly induces renal fibrosis by causing loss of mitochondrial integrity in aged Sprague-Dawley (SD) rats. To evaluate the effects of short-term HFD intake on age-associated renal fibrosis, we administered HFD in young and aged SD rats for 15 days. Our results showed that a short-term HFD significantly increased the renal fibrosis and inflammation in aged rats. Moreover, mitochondrial integrity and the expression of fatty acid oxidation-related proteins decreased in the kidneys of the HFD-fed aged rats. Further, NRK52E renal tubular epithelial cells subjected to lipid stress by treatment with oleic acid showed a reduced amount of mitochondrial OXPHOS-related proteins. Our results suggest that short-term HFD affects mitochondrial integrity and exacerbates inflammation leading to renal fibrosis, especially in aged rats. We conclude that the mitochondrial integrity in kidney tissues is important in HFD-induced renal fibrosis development during aging.
Assuntos
Dieta Hiperlipídica , Nefropatias , Animais , Dieta Hiperlipídica/efeitos adversos , Fibrose , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Human pancreatic tumor cells such as PANC-1 are known for their ability to tolerate nutrient starvation and thrive under the hypovascular tumor microenvironment, a phenomenon termed as 'austerity'. A search of agents that preferentially inhibit the cancer cell viability under the starvation condition without toxicity in the nutrient-rich condition is a promising approach in anticancer drug discovery. In this study, a triterpene lactone, 3ß-hydroxy-13,28-epoxyurs-11-en-28-one (ursenolide), isolated from a Callistemon citrinus extract has shown strong preferential cytotoxicity against PANC-1 cells under nutrient starvation with PC50 value of 0.4â µm. Ursenolide-induced rounding of PANC-1 cell morphology followed by rupture of the cell membrane leading to cell death. In a real-time cell migration study, ursenolide was found to inhibit PANC-1 cell migration significantly. Mechanistically, it inhibited GRP78 and GRP94 under the starvation condition suggesting inhibition of unfolded protein response (UPR), an adaptive process of cell survival during starvation. It also inhibited the phosphorylation of the key survival protein Akt and mTOR. Overall results suggested that ursenolide is a potential anticancer agent against pancreatic cancer.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Lactonas/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Myrtaceae/química , Neoplasias Pancreáticas/tratamento farmacológico , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Glicoproteínas de Membrana/metabolismo , Conformação Molecular , Neoplasias Pancreáticas/patologia , Desdobramento de Proteína/efeitos dos fármacos , Triterpenos/química , Triterpenos/isolamento & purificação , Células Tumorais CultivadasRESUMO
Human pancreatic cancer is resistant to almost all conventional chemotherapeutic agents. It is known to proliferate aggressively within hypovascular tumor microenvironment by exhibiting remarkable tolerance to nutrition starvation, a phenomenon termed as "austerity". Search for the new agents that eliminate the tolerance of cancer cells to nutrition starvation is a promising strategy in anticancer drug discovery. In this study, two new meroterpenoids named callistrilones O and P (1 and 2) together with eight known triterpenes (3-10) were isolated from the active dichloromethane extract of Callistemon citrinus leaves. The structure elucidation of the new compounds was achieved by HRFABMS, 1D, 2D NMR, and ECD quantum calculations. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells. Among these, callistrilone O (1) exhibited the most potent preferential cytotoxicity with a PC50 value of 0.3 nM, the strongest activity with over 2000 times potent than the positive control arctigenin. Callistrilone O (1) induced dramatic alterations in PANC-1 cell morphology leading to cell death under nutrient-deprived conditions. Compound 1 also inhibited PANC-1 cell migration and -PANC-1 colony formation under the nutrient-rich condition.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Myrtaceae/química , Neoplasias Pancreáticas/tratamento farmacológico , Terpenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Egito , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/patologia , Relação Estrutura-Atividade , Terpenos/química , Terpenos/isolamento & purificação , Microambiente Tumoral/efeitos dos fármacos , Neoplasias PancreáticasRESUMO
Human pancreatic cancer cells display remarkable tolerance to nutrition starvation that help them to survive in a hypovascular tumor microenvironment, a phenomenon known as "austerity". The elucidation of agents countering this tolerance is an established antiausterity strategy in anticancer drug discovery. In this study, a Callistemon citrinus leaf extract inhibited the viability of PANC-1 human pancreatic cancer cells preferentially under nutrient-deprived medium (NDM) with a PC50 value of 7.4 µg/mL. Workup of this extract resulted in the isolation of three new meroterpenoids, callistrilones L-N (1-3), together with 14 known compounds (4-17). The structure elucidation of the new compounds was achieved by HRFABMS and by NMR and ECD spectroscopic analysis. The new compounds showed highly potent preferential cytotoxicity against PANC-1 cells with PC50 values ranging from 10 to 65 nM in NDM. Of these, callistrilone L (1) inhibited PANC-1 cell migration and colony formation in a normal nutrient-rich condition. Callistrilone L (1) also strongly suppressed the migration of PANC-1 cells in real time. Mechanistically, 1 was found to inhibit the Akt/mTOR and autophagy activation pathway. Callistrilone L (1) and related meroterpenoids are promising leads for anticancer drug development based on the antiausterity strategy used in this work.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Myrtaceae/química , Neoplasias Pancreáticas/patologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Análise Espectral/métodosRESUMO
Cholinergic dysfunction and oxidative stress are the most common causes of Alzheimer's disease (AD). Safflower seed contains various anti-oxidant and cholinergic improvement compounds, such as serotonin and its derivatives. In the present study, we investigated the protective effects and mechanisms of a safflower seed extract on scopolamine-induced memory impairment in a mouse model. The safflower seed extract was orally administered at a dose of 100 mg kg-1 day-1, and then behavior tests (such as T-maze and novel object recognition tests) were conducted. Acetyl cholinesterase (AChE) activity, reactive oxygen species (ROS) production, and antioxidant enzymes in the brain were measured. In behavior tests, the novel route exploration and object recognition were improved by the administration of the safflower seed extract, which suggests that the safflower seed extract improves memory function in the scopolamine-treated mouse model. In addition, the safflower seed extract-administered group showed inhibition of the AChE activity and improved cholinergic dysfunction. Furthermore, the administration of the safflower seed extract resulted in lower ROS production and higher antioxidant enzyme levels as compared to the scopolamine-treated group, suggesting the protective role of the safflower seed extract against oxidative stress. The results of the present study suggest that the safflower seed extract improves scopolamine-induced memory deficits via the inhibition of cholinergic dysfunction and oxidative stress. Therefore, safflower seeds might become a promising agent for memory improvement in AD patients.
Assuntos
Carthamus tinctorius/química , Colinérgicos/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Acetilcolinesterase/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos ICR , Espécies Reativas de Oxigênio/metabolismo , Escopolamina/efeitos adversos , Sementes/químicaRESUMO
This study examined whether serotonin and two of its derivatives, N -feruloylserotonin and N -( p -coumaroyl) serotonin, have a renoprotective effect in a mouse model of cisplatin-induced acute renal failure. Cisplatin (20 mg/kg body weight) was administered by intraperitoneal injection to male BALB/c mice that had received oral serotonin, N -feruloylserotonin or N -( p -coumaroyl) serotonin (7.5 mg/kg body weight per day) during the preceding 2 days. At 3 days after the cisplatin injection, serum and renal biochemical factors, oxidative stress, inflammation and apoptosis-related protein expression were evaluated, and histological examinations were performed. Cisplatin caused reduction in body weight and an increase in kidney weight; however, N -( p -coumaroyl) serotonin and N -feruloylserotonin attenuated these effects. Moreover, the serotonin derivatives significantly decreased serum urea nitrogen and creatinine levels. They also significantly reduced the level of reactive oxygen species and upregulated the expression of glutathione peroxidase in the kidney. Furthermore, the serotonin derivatives improved the abnormal expression of mitogen-activated protein kinases activation-dependent inflammation- and apoptosis-related protein and caused less renal damage. These results provide important evidence that N -( p -coumaroyl) serotonin and N -feruloylserotonin exert a pleiotropic effect on several parameters related to oxidative stress, inflammation and apoptosis. The derivatives also have a renoprotective effect in cisplatin-treated mice; however, this effect is higher with N -( p -coumaroyl) serotonin.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Fitoterapia , Serotonina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Nitrogênio da Ureia Sanguínea , Carthamus tinctorius/química , Creatinina/sangue , Modelos Animais de Doenças , Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Inflamação/genética , Injeções Intraperitoneais , Rim/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Serotonina/administração & dosagem , Serotonina/farmacologiaRESUMO
Safflower seed is effective against oxidative stress, mediating the activation of the apoptotic signaling pathway in the renal tissues of cisplatin-treated mice. The anticancer activity of safflower in various cancer cell lines has also been reported. The present study was conducted to evaluate the potential synergistic anticancer effects of the co-treatment of safflower seed extracts and cisplatin in RKO cells and in BALB/c mice bearing RKO cell-derived human colorectal tumors. In the cellular system, RKO cells were treated with safflower seed extract in the presence or absence of cisplatin for 48 h and the cytotoxicity was evaluated by using microscopy. In the in vivo system, mice were injected with RKO cells and subsequently orally administered 100 or 200 mg/kg body weight safflower seed extract plus cisplatin-treated or untreated mice for 3 days to examine the inhibitory effect on the tumor. Treatment with safflower seed extract or cisplain to RKO cells resulted in a greater cell death than in with untreated cells. In the RKO cells co-treated with both safflower seed extract and cisplatin, greater cell damage was observed. In addition, mice co-administered safflower seed extract and cisplatin had lower concentrations of serum creatinine, which were indicative of less damage to the kidney, and had a lower solid tumor mass and higher expression of the caspase-3 protein. The results showed that safflower seed extract was highly toxic to RKO cells and inhibited tumor growth in cisplatin-treated mice through renoprotective effects.