RESUMEN
Pancreatic cancer, one of the deadliest cancers with the lowest 5-year survival rate, often develops resistance to gemcitabine-based chemotherapies. The hypovascular nature of pancreatic tumors forces cancer cells to adapt to nutrient-depleted tumor microenvironments. Conventional anticancer agents targeting rapidly dividing cancer cells under nutrient-rich conditions are largely ineffective against adapted pancreatic cancer cells. Thus, targeting cancer cells under nutrient starvation, termed the "antiausterity strategy", may be effective for pancreatic cancer. This study examined nicolaioidesin C (Nic-C) derivatives as antiausterity agents. Among the 32 derivatives, Nic-15 (4n) exhibited superior cytotoxicity against MIA PaCa-2 and PANC-1 pancreatic cancer cells, inhibited MIA PaCa-2 cell migration and colony formation, and modulated the PI3K/Akt/mTOR pathway, while reducing the ER stress markers induced by gemcitabine. Nic-15 was found to inhibit tumor growth and enhance the efficacy of gemcitabine in an in vivo xenograft model. Nic-15 in combination with gemcitabine may be an effective strategy for the treatment of pancreatic cancer.
Asunto(s)
Desoxicitidina , Gemcitabina , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos , Naftoquinonas , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Antineoplásicos Fitogénicos/farmacología , Fosfatidilinositol 3-Quinasas , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Human pancreatic tumors are hypovascular in nature, and their tumor microenvironment is often characterized by hypoxia and severe nutrient deprivation due to uncontrolled heterogeneous growth, a phenomenon known as "austerity". However, pancreatic tumor cells have the inherent ability to adapt and thrive even in such low nutrient and hypoxic microenvironments. Anticancer drugs such as gemcitabine and paclitaxel, which target rapidly proliferating cells, are often ineffective against nutrient-deprived pancreatic cancer cells. In order to overcome this limitation, the search for novel agents that can eliminate cancer cells' adaptations to nutrition starvation, also known as "antiausterity" agents, represents a promising strategy to make the cancer cells susceptible to treatment. The natural product (+)-nicolaioidesin C (Nic-C) was found to have potent antiausterity activity against the PANC-1 human pancreatic cancer cell line in a nutrient-deprived condition. However, its efficacy in vivo remained untested. To address this, we synthesized Nic-C in its racemic form and evaluated its antitumor potential in a human pancreatic cancer xenograft model. Nic-C inhibited pancreatic cancer cell migration and colony formation and significantly inhibited tumor growth in MIA PaCa-2 xenografts in a dose-dependent manner. Furthermore, Nic-C inhibited the Akt/mTOR and autophagy signaling pathways in both in vitro and in vivo studies. Metabolomic profiling of in vivo tumor samples suggests that Nic-C downregulates amino acid metabolism while upregulating sphingolipid metabolism.
Asunto(s)
Antineoplásicos Fitogénicos , Chalconas , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Xenoinjertos , Antineoplásicos Fitogénicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Microambiente TumoralRESUMEN
An n-hexane extract of Callistemon subulatus was found to exhibit potent cytotoxicity against PANC-1 human pancreatic cancer cells, preferentially under nutrition starvation conditions, with a PC50 value of 6.2 µg/mL. Phytochemical investigation of this bioactive extract resulted in the isolation of fifteen compounds (1-15), including a new compound, subulatone A (-). The structure of compound 1 was elucidated using HRFABMS and NMR spectroscopic analyses. The isolated compounds were tested for their preferential cytotoxicity against the PANC-1 human pancreatic cancer cell line, using an anti-austerity strategy. Among these, myrtucommulone A (2) showed highly potent preferential cytotoxicity, with a PC50 value of 0.28 µM. Myrtucommulone A (2) was found to alter PANC-1 cell morphology, inhibit cell migration, and downregulate the PI3K/Akt/mTOR and autophagy signaling pathways in nutrient-deprived media, leading to cancer cell death. Therefore, myrtucommulone A (2) is a lead compound for anticancer drug development based on an anti-austerity strategy.
RESUMEN
An ethanolic extract of the stem of Abies spectabilis exhibited strong cytotoxicity against MIA PaCa-2 human pancreatic cancer cells preferentially under nutrient-deprived conditions. Therefore, phytochemical investigation of this bioactive extract was carried out, and that led the isolation of ten compounds (1-10) including a new abietane-type diterpene (1). The structure of the new compound (1) was elucidated by combined spectroscopic techniques, including HRFABMS, NMR and quantum ECD calculation. All the isolated compounds were evaluated for their efficacy against MIA PaCa-2 human pancreatic cancer cell line by employing an anti-austerity strategy. Among the tested compounds, dehydroabietinol (5) displayed the most potent activity with a PC50 value of 6.6 µM. Dehydroabietinol (5) was also found to retard the MIA PaCa-2 cell migration under normal nutrient-rich conditions displaying its anti-metastatic potential. Investigation on the mechanism suggested that dehydroabietinol (5) is an inhibitor of the key cancer cell survival Akt/mTOR/autophagy signaling pathway.
Asunto(s)
Abies , Antineoplásicos Fitogénicos , Neoplasias Pancreáticas , Abietanos/farmacología , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Extractos Vegetales/uso terapéutico , Neoplasias PancreáticasRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias Pancreáticas/tratamiento farmacológico , Pregnenodionas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pregnenodionas/síntesis química , Pregnenodionas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Benzofenonas/farmacología , Betula/química , Neoplasias Pancreáticas/tratamiento farmacológico , Antineoplásicos Fitogénicos/aislamiento & purificación , Benzofenonas/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Corteza de la Planta/química , Tailandia , Microambiente Tumoral/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Pancreáticas/patología , Piper/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias Pancreáticas/tratamiento farmacológico , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Tallos de la Planta/química , TailandiaRESUMEN
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.