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.
Highlights
Breast cancer is a major public health problem and is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012 [1]
15–20% of breast tumors lacks ER, human epidermal receptor-2 (HER-2) and progesterone receptor (PR) and this subtype is classified as triple negative breast cancer (TNBC)
This drug was once considered as a promising anticancer drug, interfering with polyamine pathway and it was evaluated in Phase I/II
Summary
Breast cancer is a major public health problem and is the most common cancer in women worldwide, with nearly 1.7 million new cases diagnosed in 2012 (second most common cancer overall) [1]. Breast cancer is a heterogeneous disease and harbors different receptors and in some cases no recognized receptor driving the disease [3]. The female hormone, estrogen is implicated in the origin and progression of breast cancer and approximately 70% of breast tumors harbor the receptor protein, estrogen receptor. 15% of breast tumors harbor the human epidermal receptor-2 (HER-2). 15–20% of breast tumors lacks ER, HER-2 and progesterone receptor (PR) and this subtype is classified as triple negative breast cancer (TNBC). In the case of ERα- and HER-2 positive breast tumors, drug resistance develops in the course of therapy and new drugs are needed for treating all forms of breast cancer [12]. Research on polyamine analogues have been undertaken in this context [13,14,15,16,17]
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