Cellular and Animal Model Studies on the Growth Inhibitory Effects of Polyamine Analogues on Breast Cancer

Abstract

Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N1-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

Nanospermidine in Combination with Nanofenretinide Induces Cell Death in Neuroblastoma Cell Lines

“…Among the molecules currently used to upregulate polyamine catabolism, polyamine analogs, such as N1,N11-diethylnorspermine (DENSpm) and N1-ethyl-N11-[(cyclopropyl)m ethyl]-4,8-diazaundecane (CPENSpm), have demonstrated activity in several types of tumors [9,11,12]. However, these molecules showed some drawbacks, such as poor specificity for cancer cells, induction of epithelial-mesenchymal transition-dedifferentiation in noncancerous cells, and limited activity in clinical trials [11,12].…”

“…However, these molecules showed some drawbacks, such as poor specificity for cancer cells and induction of epithelial-mesenchymal transition-dedifferentiation in non-cancerous cells [11]. Overall, they showed poor positive outcomes in Phases I and II clinical trials [12]. A new strategy to cause cell death in tumors might be based on increasing intracellular polyamine concentrations above physiological values to induce the production of oxidation metabolites at levels exceeding cell tolerance (Figure 1).…”

Specific effects of antitumor active norspermidine on the structure and function of DNA

“…From a methodological point of view, combinatorial study with structural and functional analysis as adapted in the present study would be useful to obtain the essential features of the ligand-DNA interaction. Studies along such direction are expected to contribute for the design of novel polyamines as the candidate of potent antitumor active drug 61 .…”

Polyamines: Functions, Metabolism, and Role in Human Disease Management

“…PAs have been found to be involved in various important biochemical roles, such as synthesis, functioning, maintenance, and stability of nucleic acids (DNA and RNA), and proteins [ 11 ]. They also play a pivotal role in cell signaling, DNA binding, transcription, RNA splicing, and functioning of cytoskeletons, and Eukaryotic translation by maturing translation initiation factor 5A (eIF5A) [ 12 , 13 , 14 , 15 , 16 ]. The numbers of positively charged amino groups linked with each PA are the key factors behind the activity of PAs.…”