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

J Nat Prod. 2018 Aug 24;81(8):1877-1883. doi: 10.1021/acs.jnatprod.8b00405. Epub 2018 Aug 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / ultrastructure
  • Cell Movement / drug effects
  • Cell Size / drug effects
  • Citrus / chemistry*
  • Coumarins / isolation & purification
  • Coumarins / pharmacology
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Organelles / drug effects
  • Organelles / ultrastructure
  • Pancreatic Neoplasms / drug therapy*
  • Thailand
  • Tumor Microenvironment
  • Tumor Stem Cell Assay
  • Wound Healing / drug effects

Substances

  • Antineoplastic Agents, Phytogenic
  • Coumarins