Antitumor potential of polyamines in cancer

Abstract

The dysregulation of polyamines in tumors has made polyamine metabolism an appealing target for cancer therapy. Gene mutations drive the reprogramming of polyamine metabolism in tumors, presenting promising opportunities for clinical treatment. The proposed strategies involve inhibiting polyamine biosynthesis while also targeting the polyamine transport system as antitumor approaches. A growing number of drugs aimed at polyamine biosynthesis and transport systems are undergoing clinical trials. Polyamine metabolism plays a role in regulating cancer signaling pathways, suggesting potential combination therapies for cancer treatment. Furthermore, supplemental polyamine substances have demonstrated antitumor activity, indicating that combining polyamines with downstream targets or immunotherapy could offer significant clinical benefits. These discoveries open new avenues for leveraging polyamine metabolism in anticancer therapy.

1. Introduction

Polyamines are natural components in cells and body fluids and belong to a class of long-chain aliphatic compounds containing two or more amino groups. Important polyamines in mammals, such as putrescine, spermidine, and spermine, play crucial physiological roles. With multiple positive charges, polyamines exhibit strong affinity for nucleic acids and play a significant role in regulating processes such as replication, transcription, and cell division [1]. Polyamines are widely distributed in various animals, plants, and bacteria and play crucial roles in regulating cellular physiological functions such as cell proliferation and differentiation [2]. Furthermore, polyamines are also implicated in immune cell differentiation and the modulation of inflammatory responses [3].

Over the years, researchers have reported that polyamines are able to modulate ion channels and participate in transcriptional, translational and post-translational activities [4,5]. Additionally, polyamines are involved in regulating chromatin remodeling, eukaryotic translation initiation factor 5A (eIF-5A) hypnosis and apoptosis [6]. Intracellular polyamines are strictly regulated at millimolar concentrations through the coordination of biosynthesis, degradation metabolism, and extracellular uptake transport in a dynamic equilibrium process [7,8]. Extracellular polyamines are derived mainly from the diet, microbiota, and shed or damaged cells, where they are absorbed into the circulation or enter the cells to exert their functions [8,9]. Intracellular polyamine biosynthesis decreases with age, and supplementation with spermine and spermidine has been shown to prolong lifespan by inhibiting inflammatory responses and promoting cellular autophagy [10].

Dysregulation of polyamine metabolism is commonly observed in various tumors and is directly associated with the initiation and progression of cancer [11]. Studies have demonstrated that compared with normal cells, tumor cells exhibit elevated levels of polyamines [12,13]. Tumor cell proliferation requires an intracellular pool of polyamines for maintenance. Reducing intracellular polyamine levels in the body to enhance antitumor immune response is considered an effective antitumor strategy [14]. In addition, polyamine metabolism is interconnected with the microbiota and diet, contributing to the establishment of a tumor microenvironment that promotes cancer initiation and progression [8]. Some gene mutations and signaling pathways are involved in the regulation of polyamine metabolism disorders in tumor cells, providing rational targets for intervention in cancer therapy. In addition, recent evidence has shown that polyamines can enhance the body’s antitumor immune response, providing new evidence for the use of polyamines in cancer therapy. Therefore, new strategies for combination therapy utilizing polyamines should be explored for the treatment and prevention of multiple types of cancers.