Chemical Constituents of Thai Citrus hystrix and Their Antiausterity Activity against the PANC-1 Human Pancreatic Cancer Cell Line

Abstract

Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in a hypovascular tumor microenvironment. Searching for agents that preferentially inhibit cancer cell viability under nutrition starvation conditions is a novel antiausterity strategy in anticancer drug discovery. In the present study, a hexane extract of the peels of Citrus hystrix fruits showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells using a nutrient-deprived medium. Phytochemical investigation of this bioactive extract led to the isolation of 10 coumarins (1-10) including a new furanocoumarin (1). The isolated compounds were tested for their preferential cytotoxic activity against three different human pancreatic cancer cell lines [PANC-1, MIA PaCa-2, and PSN-1]. Among these, bergamottin (7) was identified as the most active constituent. In real-time live imaging, 7 was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (7) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, 7 inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (7) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer.

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

“…[3] Therefore, the ability of ursenolide to suppress colony formation under DMEM was investigated using the procedure described before. [7] The PANC-1 cells were plated in DMEM and treated at 0, 12.5, 25, and 50 μM of ursenolide (non-cytotoxic concentration in nutrientrich DMEM media) for 24 hours. Afterwards, the medium was replaced with fresh DMEM without the test compound, and the cells were allowed to grow and proliferate in a CO 2 incubator at 37°C for 10 days.…”

“…[33] The majority of the antiausterity agents have been found to display preferential cytotoxicity against PANC-1 human pancreatic cancer cells by downregulation of Akt/mTOR signaling under NDM. [6,7] Therefore, Akt/mTOR signaling cascade is one of the key targets in anticancer drug discovery. [34] The effect of ursenolide on the Akt/mTOR signaling pathway was investigated using Western blot experiment.…”

“…It also inhibited Akt phosphorylation. [6,23] During our search for antiausterity agents, [6][7][8][9] we found that 3β-hydroxy-13,28-epoxyurs-11-en-28-one (ursenolide; Figure 1), isolated from an active dichloromethane extract of Callistemon citrinus (CURTIS) SKEELS leaf from Egypt, inhibited PANC-1 human pancreatic cancer cells viability preferentially in nutrient-deprived medium (NDM) with a PC 50 value of 0.4 μM, while no cytotoxicity was observed in Dulbecco's modified Eagle's medium (DMEM). [24] Therefore, we investigated the effect of the ursenolide on PANC-1 human pancreatic cancer cell morphology, migration, colony formation, and the underlying mechanism with particular focus on its effect on the unfolded protein response markers (GRP78 and GRP94) and Akt/mTOR pathway.…”

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

“…In particular, a large number of coumarin derivatives with high antitumor activity have been found in recent years [7][8][9][10][11][12][13][14][15][16][17][18]. Natural derivatives of 7-hydroxycoumarin containing terpene fragments have also attracted the attention of the medicinal chemistry community [19][20][21]. The best-known compound of this structural type is auraptene (Figure 1), for which a variety of biological activities are known, including antitumor properties [22].…”

Parallel evolution of UbiA superfamily proteins into aromaticO-prenyltransferases in plants

“…interactions as well as citrus phototoxicity caused by FCs photosensitization 48 , which limits the application of citrus essential oils as cosmetic ingredients 49,50 . The diverse pharmaceutical activities of O-prenylated coumarins, often due to O-prenyl moieties [2][3][4]13,28 , suggest that the coumarin O-PT genes identified in this study could serve to produce valuable varieties of coumarins.…”