RESUMO
Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. A series of triorganotins, (trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT)) have been shown to decrease the lytic function of human NK cells. TPT and MDPT were much more effective than DMPT or TMT at reducing lytic function. This study investigates the role that decreased ATP levels may play in decreases in the lytic function of NK cells induced by these OTs. A 24 h exposure to as high as 10 muM TMT caused no decrease in ATP levels even though this level of TMT caused a greater than 75% loss of lytic function. TPT at 200 nM caused a decrease in ATP levels of about 20% while decreasing lytic function by greater than 85%. There was no association between ATP levels and lytic function for any of the compounds when NK cells were exposed for 1h or 24 h. However, after a 48 h exposure to both DMPT and TPT decreased lytic function was associated with decreased ATP levels. There was an association between decreased lytic function and decreased ATP levels after a 6 day exposure to each of the four compounds. These studies indicate that the loss of lytic function seen after 1 h and 24 h exposures to this series of organotins cannot be accounted for by decreases in ATP. However, after longer exposures loss of lytic function may be in part be attributable to inadequate ATP levels.
RESUMO
Natural killer (NK) cells are our initial immune defense against viral infections and cancer development. They are able to destroy tumor and virally infected cells. Thus, agents that are able to interfere with their function increase the risk of cancer and/or infection. Organotins (OTs) have been shown to interfere with the tumor-destroying function of human NK cells. The purpose of the current study was to explore the relationship of a series of triorganotins, that differ in structure by only a single organic group, for their capacity to block NK tumor-cell destroying (lytic) function. Here we examine the series: trimethyltin (TMT), dimethylphenyltin (DMPT), methyldiphenyltin (MDPT), and triphenyltin (TPT). NK cells were exposed to TMT, DMPT, MDPT or TPT for 1, 24, 48h, or 6d. A 1h exposure to TMT, at concentrations as high as 20µM, had no effect on lytic function. However, concentrations as low as 2.5µM were able to decrease NK tumor-destroying function after 6d. A 1h exposure to DMPT had no effect on lytic function, however, after 6d there was an 80-90% decrease in lytic function at 1µM. Exposure to MDPT (as low as 2.5µM) decreased NK function at 1h, after 6d there was as much as a 90% decrease at concentrations as low as 100nM MDPT. TPT decreased lytic function in a manner similar to MDPT, however, it was more effective at 1h than MDPT. The effect of the triorganotins on the ability of NK cells to bind to targets was studied, to determine if this contributed to the loss of lytic function. The relative immunotoxic potential of this series of compounds is TPT≈MDPT>DMPT>TMT.
