Effect of Uremic Toxins – Guanidino Compounds and Creatinine – on Proliferation of HL60 and K562 Cell Lines

Abstract

Growth of the promyelocytic cell line HL60 and the erythroleukemia cell line K562 is inhibited by ‘uremic toxins’: creatinine, guanidino propionic acid and guanidino succinic acid in a concentration range similar to that of uremic sera. Among the tested compounds, creatinine exhibits the strongest and most dose-dependent inhibitory effect on both kinds of cells. These results provide a better understanding of the mechanism involved in the anemia of uremic patients.

Effect of Uremic Serum on 1,25-Dihydroxyvitamin D₃-lnduced Differentiation of Human Promyelocytic Leukemia Cell, HL-60

“…(p<0.02; table 2). Together with the data that HL-60 cell differentiation is associated with suppression of cell prolif eration, the finding that cell numbers after 5 days of treat ment were similar in the control and uremic serum-treated cells indicates that proliferation of HL-60 cells was sup pressed by uremic serum as reported previously [18].…”

“…The results obtained from a mixing study strongly suggested the occurrence of sub stance^) which inhibited the action of l,25-(OH)2D3 on these cells. Also, a significant suppression of cell prolifera tion was observed with uremic serum treatment as pre viously described [18]. However, as HL-60 cell proliferation is not coupled to its differentiation as we [3,22] and others [29,30] have previously demonstrated, the proliferationsuppressive effect of uremic serum could be neglected in assessing the effect of I,25-(OH)2D3 on cell differentiation.…”

“…It has also been reported that chronic renal failure is associated with a significant impairment in immune poten tial which could be returned to normal by the administra tion of la-hydroxyvitamin D3 [15], and that uremic serum contains humoral factors which affect various functions of the peripheral blood mononuclear cells in vitro [16,17]. Furthermore, uremic toxins have been reported to affect proliferation of HL-60 cells [18]. Recent reports have dem onstrated the intimate involvement of l,25-(OH)2D3 in the immune system [19][20][21].…”

In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection

“…In contrast, Nathan et al [25] reported that creatinine, guanidinopropionic acid, and guanidinosuccinic acid inhibit the growth of HL-60 cells and of the erythroleukemia cell line K562. It is of note, however, that these authors applied concentrations up to 200 times higher than those used in the present study; in addition, proliferation was determined by counting the colony formation on tissue culture dishes, which is a less accurate method compared to the flow cytometric method used in this study.…”

“…Hirayama et al [24] described that a mixture of guanidino compounds suppresses the production of superoxide by normal isolated neutrophils. Furthermore, guanidino compounds such as guanidinosuccinic acid, creatinine, and guanidinopropionic acid, have been shown to inhibit HL-60 and K562 cell line proliferation [25]. Finally, Autore et al [26] reported that methylguanidine downregulates the tumor necrosis factor-a (TNF-a) release by activated macrophages, but other guanidino compounds were not evaluated.…”