Effect of swainsonine on stimulation and cell cycle progression of human lymphocytes.
The indolizidine alkaloid swainsonine (SW) is an inhibitor of lysosomal alpha-mannosidase reported to have antimetastatic activity in animal models. The cells grown in its presence develop truncated (hybrid) surface oligosaccharides that may alter their functional properties dependent on interactions of various ligands with membrane receptors. In the present study we observe that SW enhances stimulation of human lymphocytes induced by suboptimal concentration of concanavalin A. The enhancement is manifested by an increased proportion of cells undergoing transition from G0 (G1Q) to G1 and progressing through the cell cycle (S + G2 + M). In contrast, SW suppresses stimulation of lymphocytes by phytohemagglutinin, and the degree of suppression is greater when measured by the number of cells progressing through the cell cycle (S + G2 + M) than by the proportion of cells entering G1 phase. The suppression remains evident even when SW is added 12 h after phytohemagglutinin, suggesting that SW modifies membrane receptors that develop in G1 and are necessary for cell entrance to S phase. The modification of receptors by SW thus up-regulates stimulation by concanavalin A and down-regulates stimulation by phytohemagglutinin. SW has no effect on lymphocyte stimulation induced by OKT3 monoclonal antibody or on the progression of cells from three leukemic cell lines, HL-60, L1210, and MOLT-4, through the cell cycle. The present data are compatible with the possibility that the reported suppression of the growth of metastatic mouse tumors by SW may be due to the immunomodulatory properties of this alkaloid.
Myc
A
A
Sloan-Kettering Institute for Cancer Research, New York, New York 10021.
Kunicka
J E
JE
Melamed
M R
MR
Darzynkiewicz
Z
Z
D000470:Alkaloids / Q000494:pharmacology*; D000954:Antigens, Surface / Q000494:pharmacology; D002453:Cell Cycle; D003208:Concanavalin A / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D010835:Phytohemagglutinins / Q000494:pharmacology; D017026:Swainsonine
D000470:Alkaloids; D000954:Antigens, Surface; D010835:Phytohemagglutinins; D003208:Concanavalin A; D017026:Swainsonine