Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Glycopathology and glycotherapy of cancer: Ganglioside remodeling as an effective approach for differentiation therapy of cancer

H Nojiri PhD 1, H Yamana MD 2, T Suzuki PhD 1, H Isono PhD 1

1 Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko-machi, Kanagawa, Japan, 2 First Dept Surgery, Kurume University, School of Medicine, Kurume-shi, Fukuoka, Japan,

AIMS:Gangliosides are amphiphilic membrane components. Characteristic changes in ganglioside pattern, especially increases in particular gangliosides, are observed during in vitro differentiation of human cancer cells induced by differentiation agents. An appreciable increase in ganglioside GM3 with a concomitant decrease in some neolacto-series gangliosides has been observed during differentiation of the human colonic carcinoma cell line HCT 116. We have shown that such gangliosides themselves can induce terminal differentiation of cancer cells, leading to the hypothesis that specific changes of ganglioside pattern promote the differentiation of cancer cells, and that defects in ganglioside expression might be one reason for differentiation arrest of the cells at an immature stage. We have now examined whether cancer cells growing in vivo can also be induced to differentiate by artificially introducing bioactive ganglioside(s) into the cells. METHODS:Tumors of HCT 116 cells growing in nude mice were treated with brefeldin A (BFA), a fungal metabolite that has been reported to inhibit de novo biosynthesis of neolacto-series gangliosides and to increase GM3, and changes in the cell ganglioside pattern and induction of differentiation and apoptosis were examined. RESULTS:When tumors of HCT 116 cells were treated with BFA at a non-cytotoxic concentration by direct injection, growth suppression and induction of apoptosis were clearly observed. An appreciable increase in GM3 was also observed in BFA-treated tumors. HCT 116 cells pretreated with BFA lost their tumorigenicity. CONCLUSIONS:These results suggest that remodeling of the ganglioside pattern could be an effective approach for differentiation therapy of cancer.

KEY WORDS: Ganglioside, Differentiation therapy, Apoptosis, Human colonic carcinoma cell.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on differentiation therapy.