Metabolic monosaccharides altered cell responses to anticancer drugs

Abstract

Metabolic glycoengineering has been used to manipulate the glycochemistry of cell surfaces and thus the cell/cell interaction, cell adhesion, and cell migration. However, potential application of glycoengineering in pharmaceutical sciences has not been studied until recently. Here, we reported that Ac4ManNAc, an analog of N-acetyl-d-mannosamine (ManNAc), could affect cell responses to anticancer drugs. Although cells from different tissues and organs responded to Ac4ManNAc treatment differently, treated cells with increased sialic acid contents showed dramatically reduced sensitivity (up to 130 times) to anti-cancer drugs as tested on various drugs with distinct chemical structures and acting mechanisms. Neither increased P-glycoprotein activity nor decreased drug uptake was observed during the course of Ac4ManNAc treatment. However, greatly altered intracellular drug distributions were observed. Most intracellular daunorubicin was found in the perinuclear region, but not the expected nuclei in the Ac4ManNAc treated cells. Since sialoglycoproteins and gangliosides were synthesized in the Golgi, intracellular glycans affected intracellular signal transduction and drug distributions seem to be the main reason for Ac4ManNAc affected cell sensitivity to anticancer drugs. It was interesting to find that although Ac4ManNAc treated breast cancer cells (MDA-MB-231) maintained the same sensitivity to 5-Fluorouracil, the IC50 value of 5-Fluorouracil to the same Ac4ManNAc treated normal cells (MCF-10A) was increased by more than 20times. Thus, this Ac4ManNAc treatment enlarged drug response difference between normal and tumor cells provides a unique opportunity to further improve the selectivity and therapeutic efficiency of anticancer drugs.