Structure-activity relations of s-adenosylmethionine decarboxylase inhibitors on the growth of MCF-7 breast cancer cells

Abstract

SAMDC is a key enzyme in the biosynthesis of spermidine and spermine, 2 polyamines that are essential for cell proliferation. Inhibition of polyamine biosynthesis is often targeted as a therapeutic strategy to suppress cancer cell growth as these cells contain elevated levels of polyamines. We examined the effect of a new group of SAMDC inhibitors, CGP33829, CGP35753, CGP36958, CGP39937, and CGP48664, (obtained from Ciba-Geigy, Basel, Switzerland), and their parent compound, MGBG, on the proliferation of MCF-7 breast cancer cells. MGBG had minimal effects on the proliferation of MCF-7 cells up to 6 microM concentration. In contrast, CGP48664 and CGP39937, containing 2 aromatic rings that delocalize the pi electron system of the backbone of MGBG, were potent inhibitors with 50% growth inhibition at 0.5 microM concentration. Other CGP compounds were less effective in inhibiting cell growth. The ability of CGP48664 to inhibit MCF-7 cell proliferation was related to its ability to inhibit SAMDC and to consequently deplete spermidine and spermine levels in the cell. Exogenous spermidine and spermine could reverse the growth inhibitory effects of this compound. CGP compounds also increased the activity of ODC, another enzyme involved in polyamine biosynthesis. Northern blot analysis of mRNA from MCF-7 cells progressing in cell cycle after G1 synchronization did not show an increase in ODC mRNA level by CGP48664. These data demonstrate structure-activity relationships of a series of MGBG derivatives on cell growth, enzyme activities, and polyamine biosynthesis in a hormone-responsive breast cancer cell line and suggest potential application of SAMDC inhibitors as therapeutic agents.

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

“…If DFMO was added to the cells with spermidine, growth inhibition could be prevented [7]. Similarly, when spermine was included during the incubation of CGP 48664, growth inhibition was not seen [38]. These results indicate the specificity of DFMO and CGP 48664 in inhibiting the appropriate biosynthetic enzymes.…”

“…A new generation of SAMDC inhibitors was synthesized recently, and one of these compounds, referred to as CGP 48664, appears to be particularly useful as a novel cancer therapeutic agent ( fig. 3) [37,38]. MCF-7 cells treated with 1 mM DFMO or 1 mM CGP 48664 showed comparable levels of growth inhibition [39].…”

“…However, spermine levels were not significantly altered. Treatment of MCF-7 cells with CGP 48664 resulted in an 50% decrease in spermidine and spermine, but a sixfold increase in putrescine level, compared with the control [38,39]. Inhibition of SAMDC by CGP 48664 in other cell types has also resulted in compensatory increases of putrescine levels [37].…”

Estrogen‐dependent regulation of ornithine decarboxylase in breast cancer cells through activation of nongenomic cAMP‐dependent pathways

“…In HeLa, cells transfected with constructs containing 5‐deletion inserts from the ODC gene promoter, significantly decreased activity was observed after deletion of the −115 to −72 region of the promoter [31]. Previous studies have reported that 17β‐estradiol (E2) induces ODC gene expression in breast cancer cells and the rat uterus [43–48]. We have investigated the mechanism of hormone‐induced ODC gene expression in MCF‐7 breast cancer cells and E2‐induced luciferase (reporter gene) activity in cells transfected with pODC1 which contained a −164 to +29 ODC gene (human) promoter insert linked to a bacterial luciferase gene.…”

Polyamines and cancer: old molecules, new understanding

“…Agents that target other polyamine metabolic enzymes (FIG. 1) are also potent inhibitors of cancer growth in experimental model systems 19,20 , and some of these agents are either under evaluation or have been evaluated in human clinical cancer therapeutic trials 21,22 .…”