Chemical Constituents of Thai <i>Citrus hystrix</i> and Their Antiausterity Activity against the PANC‑1 Human Pancreatic Cancer Cell Line

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 <i>Citrus hystrix</i> 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 (<b>1</b>–<b>10</b>) including a new furanocoumarin (<b>1</b>). 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 (<b>7</b>) was identified as the most active constituent. In real-time live imaging, <b>7</b> was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (<b>7</b>) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, <b>7</b> inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (<b>7</b>) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer

Chemical Constituents of Thai <i>Citrus hystrix</i> and Their Antiausterity Activity against the PANC‑1 Human Pancreatic Cancer Cell Line

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 <i>Citrus hystrix</i> 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 (<b>1</b>–<b>10</b>) including a new furanocoumarin (<b>1</b>). 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 (<b>7</b>) was identified as the most active constituent. In real-time live imaging, <b>7</b> was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (<b>7</b>) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, <b>7</b> inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (<b>7</b>) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer