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 Ac(4)ManNAc, an analog of
N-acetyl-D-mannosamine (ManNAc), could affect cell responses to anticancer drugs. Although cells from different tissues and organs responded to Ac(4)ManNAc 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 Ac(4)ManNAc 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 Ac(4)ManNAc 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 Ac(4)ManNAc affected cell sensitivity to anticancer drugs. It was interesting to find that although Ac(4)ManNAc treated
breast cancer cells (MDA-MB-231) maintained the same sensitivity to
5-Fluorouracil, the IC(50) value of
5-Fluorouracil to the same Ac(4)ManNAc treated normal cells (MCF-10A) was increased by more than 20 times. Thus, this Ac(4)ManNAc 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.