Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine

Abstract

D-Glucosamine is toxic to several malignant cell lines and in vivo tumors at concentrations that have little effect upon normal host tissues. Evidence is presented to support the hypothesis that cellular membranes may be the primary targets of glucosamine's tumoricidal activity. Treatment of rat C6 glioma cells with a cytotoxic concentration of glucosamine (20 mM) caused fragmentation of rough endoplasmic reticulum, proliferation of Golgi complexes, evagination of outer nuclear and mitochondrial membranes, and the accumulation of membranous vacuoles and lipid droplets in the cytoplasm. These changes were detected within the first 3 hr after treatment of cultures with glucosamine and became increasingly severe until cell lysis occurred between 24 and 48 hr of treatment. The cytotoxicity of glucosamine was potentiated by the local anesthetic lidocaine, and by other membrane-active drugs, at concentrations that were growth inhibitory but nonlytic. Most of these drugs possessed local anesthetic activity and inhibited glioma sterol synthesis. Within the same period of time required or ultrastructural changes in cellular membranes, glucosamine inhibited the incorporation of [2-14Clacetate into sterols and into an unidentified 400-dalton lipid that migrated close to sterols on thin-layer chromatograms. This inhibition was potentiated by lidocaine and increased over the same range of D-glucosamine concentrations that led to increased cell toxicity after a 48-hr treatment. These findings suggest that the effects of glucosamine upon cellular membranes may be central to its tumoricidal activity and that glucosamine, in combination with membrane-active drugs, may be useful in the treatment of certain types of tumors, particularly those of the central nervous system.

The Inhibition of Capacitative Calcium Entry Due to ATP Depletion but Not Due to Glucosamine Is Reversed by Staurosporine

“…They went on to suggest that many of the other biological effects of glucosamine were likely to be due to ATP depletion. However, in the data presented here and in a related study by Bounelis et al 2 we did not observe significant decreases in ATP in response to short term glucosamine treatments. The difference between our findings and those reported by Hresko et al (11) would appear to be due to the provision of alternate fuels from which ATP can be generated.…”

“…In a related study by Bounelis et al, 2 we have determined that short term glucosamine inhibits capacitative Ca 2ϩ entry in Jurkat T lymphocytes, RBL-2 cells, and BHK-21 cells. In those experiments, the influx and metabolism of glucosamine was followed utilizing [ 3 H]glucosamine.…”

“…Numerous reports dating from over 40 years ago (1,2) document that dietary glucosamine is selectively toxic to some experimentally induced tumors in rodents. In addition, Marshall et al (3) determined that exogenous glucosamine induced insulin resistance in cultured adipocytes in a manner similar to that caused by hyperglycemia but at a 40-fold lower concentration than that required for glucose.…”

Glucosamine Inhibits Decidualization of Human Endometrial Stromal Cells and Decreases Litter Sizes in Mice1

“…Although GlcN is a well-tolerated monosaccharide that is naturally made from glucose and glutamine in the body [13], a few studies have reported that large doses of GlcN induce cell death in chondrocytes and several malignant cell lines [22][23][24][25]. To examine the effect of GlcN on viability of human ESCs, human ESC-Ts [26] were cultured for 3, 6, or 9 days in the presence of 0, 2.5, or 5 mM GlcN, and the MTT assay [27] was used to determine cell viability and proliferation.…”

Antitumor activities of D-glucosamine and its derivatives

“…Wang et al(2003a;2003b) reported that NAG, GlcNH 2 ⋅HCl and GlcNH 2 could induce proliferation of leukemia K562 cells and make them differentiate toward macrophage. GlcNH 2 at concentration of certain range could kill tumor cells without influencing normal cells (Friedman and Skehan, 1980). It is therefore postulated that combination of GlcNH 2 with membrane-active drugs may have the potential to kill tumor cells, especially for neuro-oncology.…”