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Polyamines and cancer: old molecules, new understanding

Key Points

  • Polyamines are naturally occurring organic cations found in plants, animals and microbes. They are formed by the enzymatic decarboxylation of the amino acids ornithine or arginine.

  • Ornithine decarboxylase (ODC) is the first enzyme in the polyamine synthesis pathway in mammals and is the target for difluoromethylornithine (DFMO), a substrate analogue and specific inhibitor that irreversibly inactivates ODC when it binds to the active site of the enzyme.

  • ODC and several other polyamine metabolic proteins are essential for normal cell and tissue functions, including growth, development and tissue repair. ODC and polyamine content are increased in many cancers arising from epithelial tissues, such as the skin and colon.

  • Polyamines exert their effects in eukaryotic cells in part by regulating specific gene expression.

  • In murine and human colonic mucosal tissue, ODC is negatively regulated by the adenomatous polyposis coli (APC) tumour-suppressor gene. APC is mutated or deleted in the germline of people with familial adenomatous polyposis (FAP), a genetic syndrome associated with a high risk of colon cancer. APC is also mutated or deleted in somatic colon epithelial cells in most sporadic, or non-genetic, forms of colon cancer.

  • Loss of APC function causes an increase in ODC activity and polyamine biosynthesis, and tumour formation in ApcMin/+ mice, a murine model of human FAP. Treatment of ApcMin/+ mice with DFMO suppresses intestinal tumour formation.

  • Several non-steroidal anti-inflammatory drugs (NSAIDs), the use of which is associated with decreased risk of epithelial cancers, activate the transcription of spermidine/spermine N1-acetyltransferase, the first enzyme in the polyamine catabolic pathway. Experimental studies indicate that combinations of DFMO and NSAIDs are potent inhibitors of colon and intestinal cancer development in murine models.

  • Clinical studies have shown that DFMO is well tolerated and can prevent the development of precancerous lesions in the skin. Several large randomized trials involving the skin, colon and other organ sites are underway.

Abstract

The amino-acid-derived polyamines have long been associated with cell growth and cancer, and specific oncogenes and tumour-suppressor genes regulate polyamine metabolism. Inhibition of polyamine synthesis has proven to be generally ineffective as an anticancer strategy in clinical trials, but it is a potent cancer chemoprevention strategy in preclinical studies. Clinical trials, with well-defined goals, are now underway to evaluate the chemopreventive efficacy of inhibitors of polyamine synthesis in a range of tissues.

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Figure 1: Polyamine metabolism in mammals.
Figure 2: Regulation of polyamine metabolism by oncogenes and tumour-suppressor genes involved in the development of colon cancer.
Figure 3: Rationale for combination chemoprevention with inhibitors of polyamine synthesis and NSAIDs.

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Acknowledgements

The authors thank K. Nicolini and M. L. Myers for editorial assistance. The work described in this review was supported in part by grants from the United States Public Health Service.

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Correspondence to Eugene W. Gerner.

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DATABASES

Cancer.gov

bladder cancer

breast cancer

cervical cancer

colon cancer

prostate cancer

skin cancer

Entrez Gene

APC

COX2

eIF4E

KRAS

MAD1

MYC

OAZ

ODC

PAO

PPARγ

OMIM

Barrett's oesophagus

Burkitt's lymphoma

familial adenomatous polyposis

FURTHER INFORMATION

Frank Meysken's home page

Arizona Cancer Center Specialized Program of Research Excellence

MD Anderson Cancer Center chemoprevention trial with DFMO

MD Anderson Cancer Center chemoprevention trial with DFMO and celecoxib

University of California, Irvine, chemoprevention trial with DFMO and sulindac

University of Rochester chemoprevention trial with DFMO

University of Wisconsin Comprehensive Cancer Center trials

Glossary

UREA CYCLE

The key metabolic pathway in mammals for eliminating cellular breakdown products containing nitrogen.

PROTEASOMAL DEGRADATION

Degradation of proteins involving the proteasome, a 26S multiprotein complex that catalyses the breakdown of polyubiquitylated proteins. Ornithine decarboxylase is the only non-ubiquitylated protein known to be degraded by the 26S proteasome.

SINGLE-NUCLEOTIDE POLYMORPHISMS

(SNPs). Single-base-pair changes in DNA that differ among individuals.

COLON POLYP

Non-invasive but neoplastic growths that develop from normal colon mucosa and that can develop into colon cancer.

TIGHT JUNCTIONS

Intercellular junctions that act as barriers to specific tissue processes.

GAP JUNCTIONS

The most widespread type of intercellular junction, involved in coupling cells both electrically and metabolically.

RIBOSOME

Particles composed of RNA and protein that are sites of protein synthesis.

PURE TONE

A single frequency tone measured as part of clinical audiometric evaluations.

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Gerner, E., Meyskens, F. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4, 781–792 (2004). https://doi.org/10.1038/nrc1454

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