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.

The Role of Tumor-Associated Macrophages in Colorectal Carcinoma Progression

“…ABHD5 is a lipolytic co-activator of adipose triglyceride lipase, which is involved in lipolysis of triglycerides into free fatty acids and diglycerides [37], and it also supports macrophage mitochondrial function as well as helps sustain the M2 phenotype [38-40]. Polyamine spermidine, a lipolytic factor, has been reported to have a strong association with various cancers [41]. A study revealed that macrophages expressing ABHD5 potentiate CRC growth through the suppression of polyamines spermidine production.…”

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

“…The polyamines putrescine, spermidine and spermine are cationic molecules that are synthesized from arginine following its conversion to ornithine and are essential for eukaryotic cell growth and differentiation (14). Functions attributed to polyamines include binding to nucleic acids and chromatin, stabilizing cellular membranes, regulating ion channels and scavenging free radicals (15). Polyamines can form hydrogen bonds with anions, such as nucleic acids, proteins and phospholipids, and lead to condensation of DNA and chromatin (16,17).…”

MYC and tumor metabolism: chicken and egg

“…They have multiple functions in the regulation of cell growth, modulation of histone acetylation levels, and intracellular signaling (Minois et al , ). Increased polyamine levels are associated with a variety of cancers, and therapeutic approaches targeting the metabolism of polyamine have been developed (Murray‐Stewart et al , ). The biosynthesis of polyamine begins from ornithine and requires decarboxylated S‐adenosyl‐methionine produced from methionine for the subsequent steps.…”