Changes in cellular glycosylation of leukemia cells upon treatment with acridone derivatives yield insight into drug action

Yini Wang, Dayoung Park, Ace G. Galermo, Dan Gao, Hongxia Liu, Carlito B Lebrilla

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

A new acridone derivative 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-acridone hydrochloride (8a) has been shown to have potent antitumor activity. In order to understand the underlying action mechanism of 8a, three compounds of the same class with structures optimized step-by-step, 9(10H)-acridone (A), 10-(3,5-dimethoxy) benzyl-9(10H)-acridone (I) and 8a, were exposed to CCRF-CEM leukemia cell to determine the N-glycosylation changes using the microfluidic HPLC-chip-TOF MS platform. N-Glycans from whole cell lysates (WCL) and cell membranes (CM) were analyzed using isomer-sensitive chip-based porous graphitized carbon nano-LC/MS. A total of 223 N-glycan compositions and 398 N-glycan compounds were identified. Comparison of the two analyses showed that more apparent changes were observed in the CM compared with WCL, suggesting that CM may be a more sensitive indicator of changes in glycosylation. Upon 8a exposure to CCRF-CEM cells, a significant decrease in high-mannose-type glycans was observed. Different expressions of oligosaccharyltransferase subunits appear to play a key functional role in regulating the hypoglycosylation and contribute to the action mechanism of 8a. Taken together our findings suggest that glycosylation is strongly affected by therapeutic potency and can be used as possible biomarkers for monitoring toxicity and antitumor activity of 8a.

Original languageEnglish (US)
Pages (from-to)2977-2988
Number of pages12
JournalProteomics
Volume16
Issue number23
DOIs
StatePublished - Dec 1 2016

    Fingerprint

Keywords

  • Acridone derivatives
  • Cell membrane
  • Glycoproteomics
  • N-glycosylation
  • OST
  • Structural isomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this