(+)-Panduratin A induces PANC-1 human pancreatic cancer cell death preferentially under nutrient starvation by inhibiting PI3K/Akt/mTOR/autophagy signaling pathway

• Published in: Phytomedicine Plus : International journal of phytotherapy and phytopharmacology Vol. 1; no. 4; p. 100101
• Main Authors: Sun, Sijia, Kim, Min Jo, Omar, Ashraf M., Phan, Nguyen Duy, Awale, Suresh
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.11.2021; Elsevier
• Subjects: (+)-Panduratin A; Anti-austerity; Boesenbergia pandurata; Pancreatic cancer; Preferential cytotoxicity; PBS; Preferential cytotoxicity; DMSO; CCK; Anti-austerity; AO; DMEM; Boesenbergia pandurata; PI3K; Pancreatic cancer; (+)-Panduratin A; NDM; mTOR; B. pandurata; EB; MPLC
• ISSN: 2667-0313; 2667-0313
• DOI: 10.1016/j.phyplu.2021.100101

Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in the hypovascular tumor microenvironment, a phenomenon also known as “austerity”. Discovery of agents that preferentially inhibit cancer cells’ tolerance to nutrition starvation is a unique anti-austerity strategy for the discovery of a new generation of anticancer agents. To discover potential anti-austerity agents from Boesenbergia pandurata against the PANC-1 human pancreatic cancer cell line exhibiting cytotoxic effects only under the nutrient-deprived conditions with little or no toxicity under normal conditions. Phytochemical investigation of B. pandurata was carried out, and preferential cytotoxicity activity of all isolated compounds against PANC-1 cells under nutrient-deprived and nutrient-rich conditions was evaluated. The most active compound, (+)-panduratin A (1), was further investigated for its effect on PANC-1 cell morphology, including live imaging, cell migration, and colony formation inhibitory activities. Finally, a mechanistic investigation was carried out to investigate the active compound's cellular targets. Phytochemical investigation led to the isolation of four compounds (1−4). Among these, (+)-panduratin A (1) was identified as the most active constituent, displaying selective cytotoxicity against PANC-1 human pancreatic cancer cell line under the nutrient-deprived conditions, with a PC50 value of 1.6 μM. (+)-Panduratin A (1) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, (+)-panduratin A (1) inhibited the PI3K/Akt/mTOR/autophagy signaling pathway. (+)-panduratin A (1) is a promising lead compound for the anticancer drug development based on the anti-austerity strategy. [Display omitted]