Targeting polyamine metabolism for cancer therapy and prevention

Abstract

The chemically simple, biologically complex eukaryotic polyamines, spermidine and spermine, are positively charged alkylamines involved in many crucial cellular processes. Along with their diamine precursor putrescine, their normally high intracellular concentrations require fine attenuation by multiple regulatory mechanisms to keep these essential molecules within strict physiologic ranges. Since the metabolism of and requirement for polyamines are frequently dysregulated in neoplastic disease, the metabolic pathway and functions of polyamines provide rational drug targets; however, these targets have been difficult to exploit for chemotherapy. It is the goal of this article to review the latest findings in the field that demonstrate the potential utility of targeting the metabolism and function of polyamines as strategies for both chemotherapy and, possibly more importantly, chemoprevention.

Keywords: cancer therapy; chemoprevention; epigenetics; polyamines; reactive oxygen species; spermine oxidase.

Figure 1. The polyamine metabolic pathway

ODC is the first rate-limiting step in polyamine biosynthesis and produces putrescine; AdoMetDC is also rate-limiting and its activity provides the aminopropyl donor for the synthesis of both spermidine and spermine; SMOX is an inducible FAD-dependent oxidase located in both the nucleus and the cytoplasm that can produce DNA damage by its production of H₂O₂; PAOX is generally a constitutively expressed, peroxisomal oxidase that is rate-limited by the availability of N¹-acetylated polyamines; SSAT is an inducible enzyme that is critical for the maintenance of polyamine homeostasis and is implicated in the cytotoxic activity of several polyamine analogs; MTA is produced from decarboxylated S-adenosylmethionine by the activity of both spermidine and spermine synthases.

Figure 2. Inhibitors of polyamine biosynthesis and transport

DFMO is an enzyme-activated irreversible inhibitor of ODC. MGBG is a potent, competitive inhibitor of AdoMetDC, but is also a potent mitochondrial toxin. SAM486A is a potent second-generation AdoMetDC inhibitor that does not exhibit mitochondrial toxicity. AMXT 1501 is a spermine conjugate inhibitor of polyamine transport. AdoDATO and AdoDATAD are inhibitors of the aminopropyltransferases spermidine synthase and spermine synthase, respectively.

Figure 3. Polyamine analogs and inhibitors of polyamine catabolism

BENSpm is a representative symmetrically substituted polyamine analog that down-regulates polyamine biosynthesis and up-regulates polyamine catabolism. CPENSpm is a representative unsymmetrically substituted analog that acts in a similar manner to BENSpm. PG-11047 and PG-11093 are conformationally restricted polyamine analogs that have demonstrated significant antitumor activity. Verlindamycin is a biguanide oligoamine that inhibits LSD1. MDL 72,527 inhibits both PAOX and SMOX.

Figure 4. Proposed mechanism by which miR-124 regulates SMOX expression in infection/inflammation-associated carcinogenesis

Infection or inflammatory stimuli induce SMOX transcription. Normally ( ), miR-124 is also transcribed and modulates the translation of SMOX, thus reducing the potential for DNA damage. However, in some infection or inflammatory pathologies (B), including H. pylori-infected individuals, the CpG islands in each of the promoters of the miR-124 loci are methylated; thus, miR-124 transcription is reduced or silenced, allowing unregulated induction of SMOX that leads to a reduction of free radical-scavenging spermine and an increase in ROS production. This increases the likelihood of oxidative DNA damage, which is known to be associated with both genetic and epigenetic modifications contributing to carcinogenesis.