Antizyme and antizyme inhibitor activities influence cellular responses to polyamine analogs

Abstract

Close structural analogs of spermidine and spermine, polyamine mimetics, are potential chemotheraputic agents as they depress cellular polyamines required for tumor growth. Specific mimetic analogs stimulate synthesis of the regulatory protein antizyme (AZ), which not only inactivates the initial enzyme in polyamine biosynthesis but also inhibits cellular uptake of polyamines. The role of AZ induction in influencing cellular uptake of representative analogs was investigated using three analogs produced by Cellgate Inc., CGC-11047, CGC-11102, and CGC-11144, which exhibit markedly distinct AZ-inducing potential. An inverse correlation was noted between the AZ-inducing activity of a compound and the steady-state levels accumulated in cells. As some tumor cells over express AZI as a means of enhancing the polyamines required for aggressive growth, analog sensitivity was examined in transgenic CHO cells expressing exogenous antizyme inhibitor protein (AZI). Although AZI over expression increased cell sensitivity to analogs, the degree of this affect varied with the analog used.

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…This greater perturbation of polyamine pools in the non-small cell lines is consistent with previous analogue studies and is most likely the result of the significantly greater increase in polyamine catabolism induced by analogue treatment of the non-small cell lines as compared to the small cell lines, which demonstrate little or no induction of either SSAT or SMO in response to analogue treatment [11,12,25,54]. Although analogue treatment of all cell types reduced ODC activity, most likely due to an increase in ODC antizyme production as previously demonstrated by Mitchell and colleagues [36,37], it is clear that the combination of decreased polyamine synthesis and increased polyamine catabolism leads to the greatest depletion of intracellular polyamines. This phenotypic difference in total polyamine depletion may have more significance in vivo than in vitro, since in the in vivo setting the availability of circulating polyamines may be able to overcome the simple down regulation of ODC exhibited by the small cell lung cancer phenotype.…”

Antizyme and antizyme inhibitor, a regulatory tango

“…This uptake activity suggested the therapeutic use of structural analogs of polyamines that cross the plasma membrane through the polyamine uptake system. While some analogs exert their cytotoxic effect by negating the function of the physiological polyamines, others that are usually the most effective analogs also stimulate antizyme production [115]. Since the effectiveness of such toxic polyamine analogs also depends on the level of antizyme inhibitor in the treated cells, an additional challenge will be to match the optimal treatment (synthesis inhibitors vs polyamine analogs or their combination) to the composition of the molecular players in the treated cells.…”

Spermidine, a sensor for antizyme 1 expression regulates intracellular polyamine homeostasis

“…AZ also feedback inhibits the uptake of polyamines by cells. Mitchell et al, 2007 showed that polyamine analogues induced AZ1 and also decreased their own uptake and the uptake of other polyamines (Mitchell et al 2007). Thus, polyamines can regulate their own synthesis and levels via AZ1.…”