Antiausterity Activity Research Articles

Chemical Constituents and Anticancer Activities of Marine-Derived Fungus Trichoderma lixii.

The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A (1), trichodermamide B (2), aspergillazine A (3), DC1149B (4), ergosterol peroxide (5), cerebrosides D/C (6/7), 5-hydroxy-2,3-dimethyl-7-methoxychromone (8), nafuredin A (9), and harzianumols E/F (10/11). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5-11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2, 4, and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC50 of 22.43 μM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not.

Substrate-Dependent Alteration in the C- and O-Prenylation Specificities of Cannabis Prenyltransferase.

CsPT4 is an aromatic prenyltransferase that synthesizes cannabigerolic acid (CBGA), the key intermediate of cannabinoid biosynthesis in Cannabis sativa, from olivetolic acid (OA) and geranyl diphosphate (GPP). CsPT4 has a catalytic potential to produce a variety of CBGA analogs via regioselective C-prenylation of aromatic substrates having resorcylic acid skeletons including bibenzyl 2,4-dihydroxy-6-phenylethylbenzoic acid (DPA). In this study, we further investigated the substrate specificity of CsPT4 using phlorocaprophenone (PCP) and 2',4',6'-trihydroxydihydrochalcone (THDC), the isomers of OA and DPA, respectively, and demonstrated that CsPT4 catalyzed both C-prenylation and O-prenylation reactions on PCP and THDC that share acylphloroglucinol substructures. Interestingly, the kinetic parameters of CsPT4 for these substrates differed depending on whether they underwent C-prenylation or O-prenylation, suggesting that this enzyme utilized different substrate-binding modes suitable for the respective reactions. Aromatic prenyltransferases that catalyze O-prenylation are rare in the plant kingdom, and CsPT4 was notable for altering the reaction specificity between C- and O-prenylations depending on the skeletons of aromatic substrates. We also demonstrated that enzymatically synthesized geranylated acylphloroglucinols had potent antiausterity activity against PANC-1 human pancreatic cancer cells, with 4'-O-geranyl THDC being the most effective. We suggest that CsPT4 is a valuable catalyst to generate biologically active C- and O-prenylated molecules that could be anticancer lead compounds.

Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach.

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.

Piper longumConstituents InducePANC-1 Human Pancreatic Cancer Cell Death under Nutrition Starvation.

Pancreatic cancer is a highly aggressive form of cancer with a poor prognosis, partly due to 'austerity', a phenomenon of tolerance to nutrient deprivation and survival in its hypovascular tumor microenvironment. Anti-austerity agents which preferentially diminish the surivival of cancer cells under nutrition starvation is regarded as new generation anti-cancer agents. This study investigated the potential ofPiper longumconstituents as anti-austerity agents. The ethanolic extract of Piper longum was found to have preferential cytotoxicity towards PANC-1 human pancreatic cancer cells in a nutrient-deprived medium (NDM). Further investigation led to the identification of pipernonaline (3) as the lead compound with the strongest anti-austerity activity, inducing cell death and inhibiting migration in a normal nutrient medium, as well as strongly inhibiting the Akt/mTOR/autophagy pathway. Therefore, pipernonaline (3) holds promise as a novel antiausterity agent for the treatment of pancreatic cancer.

Nicolaioidesin C: An Antiausterity Agent Shows Promising Antitumor Activity in a Pancreatic Cancer Xenograft Mouse Model.

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.

Dioncophyllidine E: The first configurationally semi-stable, 7,3′-coupled naphthyldihydroisoquinoline alkaloid, from Ancistrocladus abbreviatus, with antiausterity activity against PANC-1 human pancreatic cancer cells

The discovery of a new naphthylisoquinoline alkaloid, dioncophyllidine E (4), from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae) is described. Due to its rare 7,3′-coupling type, combined with the lack of an oxygen function at C-6, it is configurationally semi-stable at the biaryl axis, and thus occurs as a pair of slowly interconverting atropo-diastereomers, 4a and 4b. Its constitution was assigned mainly by 1D and 2D NMR. The absolute configuration at the stereocenter, C-3, was elucidated by oxidative degradation. The absolute axial configuration of the individual atropo-diastereomers was established by their HPLC resolution, combined with online electronic circular dichroism (ECD) investigations, providing nearly mirror-imaged LC-ECD spectra. These were assigned to the respective atropisomers by ECD comparison with a related, but configurationally stable alkaloid, ancistrocladidine (5). Dioncophyllidine E (4a/4b) exhibits a strong preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 7.4 µM, suggesting its potential as an agent against pancreatic cancer.

Chemoproteomics reveals arctigenin as a phagophore-closure blocker via targeting ESCRT-I subunit VPS28

Arctigenin is the active ingredient of the traditional medicines Arctium lappa and Fructus Arctii and has been extensively investigated for its diverse pharmacological functions, including its novel anti-austerity activity. Although several mechanisms have been proposed, the direct target of arctigenin to induce anti-austerity activity remains unclear. In this study, we designed and synthesized photo-crosslinkable arctigenin probes and utilized them in the chemoproteomic profiling of potential target proteins directly in living cells. Vacuolar protein sorting-associated protein 28 (VPS28), a key subunit of the ESCRT-I complex implicated in phagophore closure, was successfully identified. Unexpectedly, we found that arctigenin degraded VPS28 via the ubiquitin–proteasome pathway. We also demonstrated that arctigenin induces a prominent phagophore closure-blockade phenotype in PANC-1 cells. To the best of our knowledge, this is the first report of a small molecule acting as a phagophore-closure blocker and a VPS28 degrader. The arctigenin-modulating phagophore closure provides a new druggable target for cancers that rely heavily on autophagy activation and may also be used for other diseases associated with the ESCRT system.

New callistrilone epimers from Callistemon citrinus and their antiausterity activity against the PANC-1 human pancreatic cancer cell line

Phytochemical investigation of Callistemon citrinus leaves resulted in the isolation of two new structurally unique callistrilone epimers named callistrilone Q (1) and epicallistrilone Q (2). Both epimers were found to exist in the form of equilibrium conformational isomers. The structural elucidation of the new compounds was achieved by HREIMS in addition to extensive 1D and 2D NMR spectroscopic analyses. The absolute configuration was determined using computational ECD and optical rotation calculations. Both isolated compounds displayed unprecedented preferential cytotoxic activities against PANC-1 human pancreatic cancer cells at the nanomolar level. These compounds also were found to inhibit PANC-1 cell migration under normal nutrient-rich conditions. Both compounds downregulated key proteins involved in the PI3K/Akt/mTOR signaling pathway.

Benzylisoquinoline alkaloids from Nelumbo nucifera Gaertn. petals with antiausterity activities against the HeLa human cervical cancer cell line.

Ethanolic extract of Nelumbo nucifera petals showed preferential cytotoxic activity against HeLa human cervical cancer cell line with a PC50 value of 10.4μg/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 10h. 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.

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 Thai Piper ribesoides and their antiausterity activities against the PANC-1 human pancreatic cancer cell line

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.

A new anti-austerity agent, 4′-O-methylgrynullarin from Derris scandens induces PANC-1 human pancreatic cancer cell death under nutrition starvation via inhibition of Akt/mTOR pathway

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.

Anti-Austerity Activity of Thai Medicinal Plants: Chemical Constituents and Anti-Pancreatic Cancer Activities of Kaempferia parviflora

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 β-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.

Panduratins Q–Y, dimeric metabolites from Boesenbergia rotunda and their antiausterity activities against the PANC-1 human pancreatic cancer cell line

A methanolic extract of the rhizomes of Boesenbergia rotunda showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient deficiency conditions with a PC50 value of 6.6 μg/mL. Bioactivity-guided phytochemical investigation of the rhizomes of B. rotunda led to the isolation of nine undescribed dimeric metabolites, panduratins Q–Y. Their structures were elucidated based on NMR, MS, and ECD spectroscopic data interpretation. Panduratins Q–S and U–W exhibited potent cytotoxicity towards PANC-1 cell line with the PC50 values ranging from 0.8 to 6.3 μM. Panduratin W, which possessed a cyclohexenylchalcone-linked flavanone skeleton, showed the most cytotoxicity with a PC50 value of 0.8 μM under nutrient-deprived medium.

Mitochondrial Targeting in an Anti-Austerity Approach Involving Bioactive Metabolites Isolated from the Marine-Derived Fungus Aspergillus sp.

The tumor microenvironment is a nutrient-deficient region that alters the cancer cell phenotype to aggravate cancer pathology. The ability of cancer cells to tolerate nutrient starvation is referred to as austerity. Compounds that preferentially target cancer cells growing under nutrient-deficient conditions are being employed in anti-austerity approaches in anticancer drug discovery. Therefore, in this study, we investigated physcion (1) and 2-(2′,3-epoxy-1′,3′,5′-heptatrienyl)-6-hydroxy-5-(3-methyl-2-butenyl) benzaldehyde (2) obtained from a culture extract of the marine-derived fungus Aspergillus species (sp.), which were isolated from an unidentified marine sponge, as anti-austerity agents. The chemical structures of 1 and 2 were determined via spectroscopic analysis and comparison with authentic spectral data. Compounds 1 and 2 exhibited selective cytotoxicity against human pancreatic carcinoma PANC-1 cells cultured under glucose-deficient conditions, with IC50 values of 6.0 and 1.7 µM, respectively. Compound 2 showed higher selective growth-inhibitory activity (505-fold higher) under glucose-deficient conditions than under general culture conditions. Further analysis of the mechanism underlying the anti-austerity activity of compounds 1 and 2 against glucose-starved PANC-1 cells suggested that they inhibited the mitochondrial electron transport chain.

Resignifying occupation: territorialization, place and transgression in the anti-corporatization movement at Seoul National University

ABSTRACT Occupation is a common strategy, including in anti-austerity movements. This paper examines the 2011 occupation at Seoul National University (SNU), which had an ambivalent position on anti-austerity activism, and mixed outcomes. The student occupiers held an occupied administrative building longer than previous student occupations, and their tactics were taken up by student activists around South Korea. However, the SNU occupation failed to influence the university’s corporatization. Both the successes and failures of the SNU occupation related to their resignification of ‘occupation’ relative to their subjectivity as SNU students, and from the way they enacted territorialization of the occupied administrative building. The resignification served to mobilize SNU students, but also masked the occupation’s leaders’ failure to negotiate the differences in their goals and refusal to connect with other constituencies against university austerity.

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.

Antiausterity Activity of Secondary Metabolites from the Roots of Ferula hezarlalehzarica against the PANC-1 Human Pancreatic Cancer Cell Line.

Human pancreatic cancer is one of the most aggressive types of cancer, with a high mortality rate. Due to the high tolerance of such cancer cells to nutrient starvation conditions, they can survive in a hypovascular tumor microenvironment. In this study, the dichloromethane extract of the roots of Ferula hezarlalehzarica showed potent preferential cytotoxic activity with a PC50 value of 0.78 μg/mL. Phytochemical investigation of this extract led to the isolation of 18 compounds, including one new sesquiterpenoid (6) and one new monoterpenoid (18). All isolated compounds were evaluated for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells by employing an antiausterity strategy. Among them, ferutinin (2) was identified as the most active compound, with a PC50 value of 0.72 μM. In addition, the real-time effect of ferutinin (2) and compound 6 against PANC-1 cells, exposed to a nutrient-deprived medium (NDM), showed cell shrinkage, leading to cancer cell death within a short period of exposure. Compounds 2 and 6 also inhibited colony formation of PANC-1 cells. The present study indicates that the dichloromethane extract of the roots of F. hezarlalehzarica is a rich source of bioactive compounds for targeting PANC-1 cells.

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.

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.