Polyamine metabolism and cancer: treatments, challenges and opportunities

Abstract

Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN-PI3K-mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy.

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy

“…2A). Cisplatin and doxorubicin increased total ODC protein at early timepoints (8 hours), consistent with a stress response (22), but led to decreased ODC and increased ARG2 at later timepoints (Fig. 3A).…”

“…Targeting ODC and polyamine synthesis is an attractive antitumor target since high levels of polyamines have been measured in multiple tumor types, and are necessary for transformation and progression (14,17,22). DFMO is approved for treatment of trypanosomiasis and facial hirsutism, and is in clinical trials for treatment or prevention of various tumor types (22). DFMO is of particular chemotherapeutic interest in MYCN-amplified neuroblastoma, where Myc-driven overexpression of ODC contributes to tumor hyperproliferation (24).…”

“…9, F and G) indicate that this molecular subtype of breast cancer is especially reliant on de novo polyamine biosynthesis, since in many other cell types, targeting polyamine synthesis is not effective unless combined with a polyamine uptake inhibitor (15). While the specific polyamine transport mechanisms are not well defined (22), it will be interesting to investigate the expression and function of polyamine transporters in TNBC, as deficiencies in transport systems may contribute to a more pronounced reliance on intracellular biosynthesis. Further characterization of polyamine metabolism and the effects of DFMO treatment in TNBC will help identify why this subtype is particularly sensitive.…”

“…Combined inhibition of polyamine uptake and synthesis results in antiproliferative effects in breast cancer cell lines and mouse models, suggesting that targeting polyamine metabolism may be therapeutically effective in breast cancer patients (20,21). Although drugs that target polyamine metabolism have not yet been approved for therapeutic use in cancer, clinical trials using polyamine uptake and synthesis inhibitors are underway for a number of indications, although to date none in breast cancer (22). Here we show that polyamine synthesis is suppressed in response to DNA damaging chemotherapy through the proteasomal degradation of ODC.…”

Gene expression profiling in aggressive digital papillary adenocarcinoma sheds light on the architecture of a rare sweat gland carcinoma

“…SMS is involved in polyamine metabolism. Dysregulation of polyamine metabolism has been reported to be associated with carcinogenic risk and targeting of this metabolism has raised hope of a cancer therapy . Vascular endothelial growth factor signalling is well established to have a critical function in tumour angiogenesis.…”