Possible synergy between nimbolide and chloroquine as pancreatic cancer therapeutics?

Nimbolide is a phytochemical extracted from the leaves and flowers of the neem tree (Azadirachta indica) native to India. When applied to pancreatic cancer cell lines in vitro it was found to increase the production of reactive oxygen species (ROS) and lead to apoptosis. In a pancreatic cancer cell line mouse xenograft model nimbolide was found to inhibit the phosphorylation of the AKT pathway of the pancreatic cancer cells and lead to a significant decrease in tumour volume [1]. These effects were found to be independent of autophagy induction. These are promising preclinical results. Furthermore nimbolide’s inhibition of the AKT pathway suggests a possible synergistic combination with chloroquine which was recently found to promote lysosomal cell death [2].

Chloroquine has been shown to promote the cell death of KRAS activated cancers such as pancreatic cancer independently of autophagy (see here). A recent paper has shown that in bladder cancer inhibition of the AKT pathway in combination with chloroquine is synergistic due to the enhancement of chloroquine mediated lysosomal cell death [2]. In pancreatic cancer nimbolide appears to inhibit the AKT pathway raising the possibility that chloroquine will synergise with nimbolide via enhanced lysosomal cell death. Figure 5d of ref [2] is not inconsistent with this. This would be an interesting avenue of future research.

Refs

  1. Subramani, Ramadevi, Elizabeth Gonzalez, Arunkumar Arumugam, Sushmita Nandy, Viviana Gonzalez, Joshua Medel, Fernando Camacho, et al. ‘Nimbolide Inhibits Pancreatic Cancer Growth and Metastasis through ROS-Mediated Apoptosis and Inhibition of Epithelial-to-Mesenchymal Transition’. Scientific Reports 6 (25 January 2016): 19819. doi:10.1038/srep19819.
  2. King, M A, I G Ganley, and V Flemington. ‘Inhibition of Cholesterol Metabolism Underlies Synergy between mTOR Pathway Inhibition and Chloroquine in Bladder Cancer Cells’. Oncogene, 8 February 2016. doi:10.1038/onc.2015.511.

 

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