Inhibition of N-Glycosylation towards Novel Anti-Cancer Chemotherapeutics (original) (raw)

2018, Journal of Molecular Pharmaceutics & Organic Process Research

Cell surface polysaccharides play important roles in numerous biological processes in living organisms such as maintenance of outer membrane integrity, mediators of host-pathogen interactions, cell-cell-adhesion and recognition, protein folding, cell signaling, and trafficking of proteins translated within the rough endoplasmic reticulum (ER) to the Golgi. Furthermore, abnormal glycosylation of cell surface proteins takes place during which normal cells progress to a malignant neoplastic state [1]. Thus, the modification of cell surface glycosylation is a characteristic of many cancer cells [2-4]. Many of the recently developed tumor markers are carbohydrate antigens. Identification of cell type-specific or tissue-specific glycoconjugates (tumor markers) has lead to the discovery of new assay systems or diagnosis for certain cancers via immunodetection reagents [1]. On the other hand, anti-glycan antibodies have a limited application for cancer treatment, despite the fact that a great number of tumor-associated glycans have been identified with the help of modern glycomic approaches [6]. In the last two decades, a few monoclonal antibodies targeting ganglioside GD 2 or GD 3 and a cancer vaccine with N-glycolylated ganglioside GM 3 have been developed into clinical trials. As such, changes and diversification of the expression profile of cell surface glycans based on the underlying glycobiology have received much attention from the scientific community [1]. Two of the most abundant forms of glycosylation occurring on proteins destined to be secreted or membrane-bound proteins are N-linked (to Asp (N), N-glycosylation) and mucin-type O-linked (to Ser/Thr, Oglycosylation). O-Linked glycosylation is an evolutionarily conserved protein modification found across species such as mammals, worms, insects, protozoa, and certain types of fungi, whereas N-linked glycosylation occurs in eukaryotes and widely in archaea, but very rarely in bacteria. Recent studies of cancer immunotherapy are based on immunogenicity of truncated O-glycan chains (e.g. Tn, sTn, T, and sLe a/x). Despite the importance of N-linked glycans in transformation-associated glycosylation changes for normal cells to develop tumor cells, therapeutic antibodies against N-linked glycans have not yet been developed. It may largely be attributable to the lack of specificity of N-linked glycans between normal and malignant cells. Abnormal (increased) branching of N-linked glycans has been observed in certain solid cancer cells. Altered glycosylation of N-linked glycans in cancers is typically associated with upregulation of β1,6-N-acetylyglucosaminyltransferase-5 (GnT5), enhancing β1,6-branching. Although it is an extremely challenging subject to discover druglike glycosyltransferases to block the biosynthesis of specific branching processes in cancer cells, N-glycan biosynthesis can be terminated by inhibition of the first committed enzyme, dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) activity [7-11].