Nexrutine® is an extract from the bark of the Amur cork tree Phellodendron amurense (figure 1), a source used in traditional Chinese medicine. In pancreatic cancer cell lines Nexrutine® induced apoptosis and reduced the activity of STAT3 and NF-κB . This is important as STAT3 and NF-κB promote epithelial mesenchymal transition (EMT) in pancreatic cancer, a contributor to fibrosis which reduces the penetrance of drugs.
|Figure 1: Amur cork tree Phellodendron amurense. Credit: Romana Klee. No changes were made. Creative Commons Attribution-ShareAlike 2.0 Generic (CC BY-SA 2.0).|
STATs are transcription factors which are normally present in the cytoplasm and activated by inflammatory signalling associated with EMT which leads to their nuclear import . STAT3 expression is maintained and constitutive activation has been reported in at least 30% of pancreatic cancers . Likewise transcription factor NF-κB is constitutively active in pancreatic ductal adenocarcinoma (PDAC) and promotes EMT . The EMT enhances the drug resistance of cancer cells. It could therefore be predicted that Nexrutine® would enhance the effectiveness of chemotherapeutics.
Indeed in PDAC cell lines it was found that Nexrutine® enhanced sensitivity to the standard chemotherapeutic gemcitabine . The potential anti-fibrotic mechanism of action of Nexrutine® should be investigated further as the stromal environment of pancreatic cancer is also a major obstacle facing the new class of immunotherapeutics in addition to traditional drugs.
- Gong, J., J. Xie, R. Bedolla, P. Rivas, D. Chakravarthy, J. W. Freeman, R. Reddick, et al. ‘Combined Targeting of STAT3/NF- B/COX-2/EP4 for Effective Management of Pancreatic Cancer’. Clinical Cancer Research 20, no. 5 (1 March 2014): 1259–73. doi:10.1158/1078-0432.CCR-13-1664.
- Kaplan, Mark H. ‘STAT Signaling in Inflammation’. JAK-STAT 2, no. 1 (January 2013): e24198. doi:10.4161/jkst.24198.
- Corcoran, R. B., G. Contino, V. Deshpande, A. Tzatsos, C. Conrad, C. H. Benes, D. E. Levy, J. Settleman, J. A. Engelman, and N. Bardeesy. ‘STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis’. Cancer Research 71, no. 14 (15 July 2011): 5020–29. doi:10.1158/0008-5472.CAN-11-0908.
- Maier, Harald J., Uta Schmidt-Strassburger, Margit A. Huber, Eva M. Wiedemann, Hartmut Beug, and Thomas Wirth. ‘NF-kappaB Promotes Epithelial-Mesenchymal Transition, Migration and Invasion of Pancreatic Carcinoma Cells’. Cancer Letters 295, no. 2 (28 September 2010): 214–28. doi:10.1016/j.canlet.2010.03.003.
- Gong, Jingjing, Amanda R. Muñoz, Subramanya Pingali, Florastina Payton-Stewart, Daniel E. Chan, James W. Freeman, Rita Ghosh, and Addanki P. Kumar. ‘Downregulation of STAT3/NF-κB Potentiates Gemcitabine Activity in Pancreatic Cancer Cells’. Molecular Carcinogenesis, 21 May 2016. doi:10.1002/mc.22503.