Benzophenones from Betula alnoides with Antiausterity Activities against the PANC-1 Human Pancreatic Cancer Cell Line.

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.

Chemical constituents of Callistemon citrinus from Egypt and their antiausterity activity against PANC-1 human pancreatic cancer cell line.

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.

Highly Potent Antiausterity Agents from Callistemon citrinus and Their Mechanism of Action against the PANC-1 Human Pancreatic Cancer Cell Line.

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.

A Triterpene Lactone from Callistemon citrinus Inhibits the PANC-1 Human Pancreatic Cancer Cells Viability through Suppression of Unfolded Protein Response.

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 0.4 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.

Chemical Constituents of Anneslea fragrans and Their Antiausterity Activity against the PANC-1 Human Pancreatic Cancer Cell Line.

An ethanolic extract of Anneslea fragrans leaves showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition, with a PC50 value of 9.6 µg/mL. Phytochemical investigation of this active extract led to the isolation of two new secondary metabolites, fragranones A (1) and B (2), along with 15 previously reported compounds. The structure elucidation of the new compounds was achieved by HRFABMS, acid hydrolysis, NMR, and ECD spectroscopic analysis. Fragranone A (1) is the first example of a rare natural product bearing an acetonide glucose moiety. Fragranone B (2) is representative of a rare class of natural products with a threonolactone unit linked to a chalcone through an ether linkage. The isolated compounds exhibited antiausterity activity against PANC-1 cells under nutrient-deprived conditions, and betulin (14) was found to be the most potent compound tested, with a PC50 value of 8.4 µM. In addition, fragranone A (1) was found to suppress PANC-1 cancer cell migration in real time.

Highly oxygenated antiausterity agents from the leaves of Uvaria dac.

From the chloroform extract of the leaves of Uvaria dac, four new highly-oxygenated cyclohexene derivatives named uvaridacols I-L (1-4) were isolated together with nine previously reported compounds (5-13). Their structures were determined based on the extensive NMR spectroscopic data and circular dichroism spectroscopic analysis. Among the new compounds, uvaridacol L (4) displayed strong preferential cytotoxicity in the nutrient deprived medium against five different tested pancreatic cancer cell lines, PANC-1 (PC50, 20.1µM), PSN-1 (PC50, 9.7µM), MIA PaCa-2 (PC50, 29.1µM), Capan-1 (73.0µM) and KLM-1 (25.9µM).

Chemical Constituents of Callistemon subulatus and Their Anti-Pancreatic Cancer Activity against Human PANC-1 Cell Line.

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.

A new flavanone derivative from the rhizomes of Boesenbergia pandurata.

From the methanolic extract of the rhizomes of Boesenbergia pandurata, a new flavanone derivative named (2R,7″S)-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).

Chemical constituents from Artemisia vulgaris and their antiausterity activities against the PANC-1 human pancreatic cancer cell line.

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.

Fragranone C: a new dihydrochalcone glucopyranoside from Anneslea fragrans twigs.

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].

The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence.

Reactive oxygen species (ROS) are common products of mitochondrial oxidative phosphorylation, xenobiotics metabolism and are generated in response to several environmental stress conditions. Some of them play important biochemical roles in cellular signal transduction and gene transcription. On the other hand, ROS are known to be involved in a wide range of human diseases, including cancer. The excessive production of such ROS together with disruption of homeostasis detoxifying mechanisms can mediate a series of cellular oxidative stresses. The oxidative stress of redundant free radicals production can lead to oxidative denaturation of cellular macromolecules including proteins, lipids and DNA. Moreover, oxidative damage is one of the major causes of DNA mutations, replication errors and genomic abnormalities which result in either inhibition or induction of transcription, and end with the disturbance of signal transduction pathways. Among affected signaling pathways are redox-sensitive kinases. The stimulation of these kinases induces several transcription factors through the phosphorylation of their module proteins. The activation of such pathways induces proliferation and cellular transformation. A diet rich in antioxidant compounds has potential health benefits, and there is a growing interest in the role of natural antioxidants in nutrition for prevention and cure of cancer diseases. A controversy has risen regarding the relation between antioxidants and the significant decrease in the risk of cancer incidence. In this review, we will focus on redox-sensitive kinases signaling pathways, highlighting the effects of dietary antioxidant on the prevention, incidence, prognosis or even treatment of human cancers. In addition, we will place emphasis on the chemical classes of pterocarpans as natural anti-oxidants/cancers as well as their underlying mechanisms of action, including their effects on MAPKs and topoisomerase activities.