Abstract
Metastatic human pancreatic cancer cells (the SW1990 line) that are resistant to the EGFR-targeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-O-Bu3ManNAc, a “metabolic glycoengineering” drug candidate that increased sialylation by ∼12-fold. Consistent with genetic methods previously used to increase EGFR sialylation, this small molecule reduced EGF binding, EGFR transphosporylation, and downstream STAT activation. Significantly, co-treatment with both the sugar pharmacophore and the existing TKI drugs resulted in strong synergy, in essence re-sensitizing the SW1990 cells to these drugs. Finally, l,3,4-O-Bu3ManNAz, which is the azido-modified counterpart to l,3,4-O-Bu3ManNAc, provided a similar benefit thereby establishing a broad-based foundation to extend a “metabolic glycoengineering” approach to clinical applications.
Highlights
Metastatic human pancreatic cancer cells that are resistant to the EGFRtargeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-OBu3ManNAc, a “metabolic glycoengineering” drug candidate that increased sialylation by ∼12fold
We have previously shown that cellular responses elicited by short chain fatty acid (SCFA)-modified ManNAc,[17,22,26] which include down-regulation of NF-κB and metastatic oncogenes,[27] have potential anti-cancer properties.[13,28]
Of particular relevance to our efforts to develop glycosylation-based therapies for chemotherapy-resistant pancreatic cancer, we found that epidermal growth factor receptor (EGFR) in SW1990 cells treated with l,3,4-O-Bu3ManNAc experienced an increase in sialylation of 2-fold or higher by using mass spectrometry-based “glycosite”[36] and glycan analysis methods similar to those already reported[34,37]
Summary
Metastatic human pancreatic cancer cells (the SW1990 line) that are resistant to the EGFRtargeting tyrosine kinase inhibitor drugs (TKI) erlotinib and gefitinib were treated with 1,3,4-OBu3ManNAc, a “metabolic glycoengineering” drug candidate that increased sialylation by ∼12fold.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
