Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

Abstract

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

Bisethylnorspermine Lipopolyamine as Potential Delivery Vector for Combination Drug/Gene Anticancer Therapies

“…Studies show that polyamine metabolism is dysregulated in many types of cancer, leading to polyamine levels significantly higher than in normal tissues (7,8). It was also suggested that the polyamine pathway is a distal downstream target for a number of validated oncogenes and that inhibition of polyamine synthesis disrupts the action of those genes (1,9,10).…”

Knockdown of ornithine decarboxylase antizyme 1 causes loss of uptake regulation leading to increased N 1, N 11-bis(ethyl)norspermine (BENSpm) accumulation and toxicity in NCI H157 lung cancer cells

“…It also has been previously stated that polyamine analogues such as BENSpm can actually limit their own uptake by their ability to induce antizyme and so downregulate additional polyamine uptake (Mitchell et al 2007b). In this case, the loss of AZ1 results in loss of uptake regulation, resulting in increased BENSpm uptake, accumulation, and subsequent toxicity in AZKD cells compared to SCR clones.…”

Evidence of a Role for Antizyme and Antizyme Inhibitor as Regulators of Human Cancer

“…These effects are expected to be somewhat transitory, however, since increased polyamine uptake will induce expression of antizyme, which will inhibit polyamine transport. The ratio of AZ:AZI within the cell will determine the precise effect on polyamine transport following an increase in AZI levels (60). Numerous experiments thus far have shown that constitutive overexpression of AZI results in increased polyamine uptake and increased accumulation of polyamine analogs (36, 61).…”