Long pepper extract Piperlongumine unbalances the redox state in pancreatic cancer leading to cell death

 

Piperlongumine is an extract from the fruit of the long pepper (Piper longum), each about the size of a poppy seed embedded in the surface of a flower spike (Figure 1).  Long pepper has a taste similar to, but hotter than black pepper. See here for Nigel Slater’s fruit salad with long pepper cream. Interestingly, the first known reports of Long pepper describe it as a medicament rather than a spice [1]. It is now known to increase the levels of reactive oxygen species (ROS) in cancer cells.

 

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Figure 1: Flower spikes of the long pepper (Piper longum). Credit: Charles Haynes. No changes were made. Creative Commons Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0).

 

ROS are chemically active species containing oxygen such as H2O2.  High levels of ROS induce a stress response in normal cells that can lead to cell death. The metabolism of cancer cells generates levels of ROS that would be toxic to normal cells, however cancers with mutant KRAS oncogene (present in up to 90% of pancreatic ductal adenocarcinoma (PDAC)) remove the ROS by coordinating a balanced generation of antioxidants [2].

 

It has been found in pancreatic cancer cell lines and a mouse xenograft model that Piperlongumine raised ROS levels resulting in reduced cell viability and tumour volume [3]. It is thought that Piperlongumine mediates ROS generation by inhibiting antioxidant production. Interestingly a recent paper has found that ablating the KRAS inducible antioxidant regulator NRF2, which normally keeps ROS levels low, also reduced tumour volume of human pancreatic cancer cell line mouse xenografts [4]. These results suggest that upsetting the redox balance of pancreatic cancer is a promising therapeutic strategy. 

 

Refs

 

  1. MagueKong, Bo, Chengjia Qia, Mert Erkan, Jörg Kleeff, and Christoph W. Michalski. lonne Toussaint-Samat, Anthea Bell, tr. The History of Food, revised ed. 2009
  2. Kong, Bo, Chengjia Qia, Mert Erkan, Jörg Kleeff, and Christoph W. Michalski. ‘Overview on How Oncogenic Kras Promotes Pancreatic Carcinogenesis by Inducing Low Intracellular ROS Levels’. Frontiers in Physiology 4 (2013). doi:10.3389/fphys.2013.00246.
  3. Dhillon, Harsharan, Shireen Chikara, and Katie M. Reindl. ‘Piperlongumine Induces Pancreatic Cancer Cell Death by Enhancing Reactive Oxygen Species and DNA Damage’. Toxicology Reports 1 (2014): 309–18. doi:10.1016/j.toxrep.2014.05.011.
  4. Chio, Iok In Christine, Seyed Mehdi Jafarnejad, Mariano Ponz-Sarvise, Youngkyu Park, Keith Rivera, Wilhelm Palm, John Wilson, et al. ‘NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer’. Cell, July 2016. doi:10.1016/j.cell.2016.06.056.
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