Antizyme induction by polyamine analogues as a factor of cell growth inhibition

Abstract

The polyamines spermidine and spermine and their diamine precursor putrescine are essential for mammalian cell growth and viability, and strategies are sought for reducing polyamine levels in order to inhibit cancer growth. Several structural analogues of the polyamines have been found to decrease natural polyamine levels and inhibit cell growth, probably by stimulating normal feedback mechanisms. In the present study, a large selection of spermine analogues has been tested for their effectiveness in inducing the production of antizyme, a key protein in feedback inhibition of putrescine synthesis and cellular polyamine uptake. Bisethylnorspermine, bisethylhomospermine, 1,19-bis-(ethylamino)-5,10,15-triazanonadecane, longer oligoamine constructs and many conformationally constrained analogues of these compounds were found to stimulate antizyme synthesis to different levels in rat liver HTC cells, with some producing far more antizyme than the natural polyamine spermine. Uptake of the tested compounds was found to be dependent on, and limited by, the polyamine transport system, for which all these have approximately equal affinity. These analogues differed in their ability to inhibit HTC cell growth during 3 days of exposure, and this ability correlated with their antizyme-inducing potential. This is the first direct evidence that antizyme is induced by several polyamine analogues. Selection of analogues with this potential may be an effective strategy for maximizing polyamine deprivation and growth inhibition.

Regulation of cell proliferation by the antizyme inhibitor: evidence for an antizyme-independent mechanism

“…Interestingly, cyclin D1 was also diminished in these cells whereas cyclin A levels were not affected. Similar results were found in rat HTC cells (data not shown), a cell line commonly used for studies on the antizyme and AZI pathways (Mitchell et al, 2002;Murakami et al, 1996). Thus, levels of cyclin D1 decrease when AZI expression is suppressed.…”

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

“…In addition to its role in regulating ODC activity and degradation, antizyme was also demonstrated to regulate polyamine transport across the plasma membrane via a yet unknown mechanism Mitchell et al, 1994;Suzuki et al, 1994;Sakata et al, 2000). In accordance with these observations, recent studies have established that Az may act as a tumor suppressor, as its induction is associated with growth inhibition (Mitchell et al, 2002), while its overexpression increases apoptosis and reduces tumorigenesis (Feith et al, 2001;Fong et al, 2003).…”

Role of p53/p21Waf1/Cip1 in the regulation of polyamine analogue-induced growth inhibition and cell death in human breast cancer cells

“…29 Studies by several other groups have demonstrated that inhibition of ODC by DFMO led to G 1 arrest in a variety of cell lines including tumor cells. [30][31][32] Both oligoamines and BENSpm profoundly decrease ODC activity within 24 h in MCF-7 cells, potentially through the activation of the ODC inhibitor, antizyme (AZ), 18,33 implying that downregulation of ODC could be one mechanism leading to G 1 arrest. In contrast, CHENSpm differs from BENSpm only at the terminally modified cycloheptylmethyl group, but leads to a G 2 /M arrest.…”