Cytomodulation of interleukin-2 effect by L-2-oxothiazolidine-4-carboxylate on human malignant melanoma.
Glutathione (GSH), the most prevalent intracellular non-protein thiol, plays an important role in the interleukin-2 (IL-2)-induced proliferative activity of normal and tumour cells expressing IL-2 receptor (IL-2R). In the present study, we investigate the effect of IL-2 on proliferation of the human melanoma A375 cell line, and the possible selective cytomodulation effect of this cytokine by L-2-oxothiazolidine-4-carboxylate (OTZ) on these melanoma cells and on human peripheral blood mononuclear cells (PBMCs). We found that recombinant IL-2 (rIL-2) significantly increased the proliferation rate of A375 melanoma cells, which was associated with an increase in GSH levels, the enhancement of IL-2Ralpha expression and the endogenous production of IL-2 in these tumour cells. In contrast, OTZ decreased GSH content and the proliferation rate of A375 cells, and abrogated the growth-promoting effects of rIL-2. Thus, compared to cells treated with rIL-2, pre-treatment with OTZ reduced IL-2Ralpha expression, and also decreased the consumption of rIL-2 and the endogenous secretion of IL-2 by these tumour cells. With regard to PBMCs, the combination of OTZ plus rIL-2 resulted in a more rapid and greater increase of IL-2Ralpha expression than rIL-2 alone, with the proliferation rate being similar in the first 24 h, but with a lower PBMC' count found thereafter compared to rIL-2 treatment alone. These results suggest that OTZ plays a crucial role in obtaining a selective cytomodulation of rIL-2, enabling it to exert its growth-promoting effect on normal cells, but not on melanoma cells, thereby possibly improving biochemotherapy with rIL-2.
del Olmo
Maite
M
Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Vizcaya, Spain.
Alonso-Varona
Ana
A
Castro
Begoña
B
Bilbao
Pedro
P
Palomares
Teodoro
T
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D011355:Prodrugs / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007376:Interleukin-2; D011355:Prodrugs; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D053778:Thiazolidines; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid