The Anti-Cancer Activity of the Naturally Occurring Dipeptide Carnosine: Potential for Breast Cancer

Abstract

Carnosine is an endogenous dipeptide composed of β-alanine and L-histidine, possessing a multimodal pharmacodynamic profile that includes anti-inflammatory and anti-oxidant activities. Carnosine has also shown its ability to modulate cell proliferation, cell cycle arrest, apoptosis, and even glycolytic energy metabolism, all processes playing a key role in the context of cancer. Cancer is one of the most dreaded diseases of the 20th and 21st centuries. Among the different types of cancer, breast cancer represents the most common non-skin cancer among women, accounting for an estimated 15% of all cancer-related deaths in women. The main aim of the present review was to provide an overview of studies on the anti-cancer activity of carnosine, and in particular its activity against breast cancer. We also highlighted the possible advantages and limitations involved in the use of this dipeptide. The first part of the review entailed a brief description of carnosine's biological activities and the pathophysiology of cancer, with a focus on breast cancer. The second part of the review described the anti-tumoral activity of carnosine, for which numerous studies have been carried out, especially at the preclinical level, showing promising results. However, only a few studies have investigated the therapeutic potential of this dipeptide for breast cancer prevention or treatment. In this context, carnosine has shown to be able to decrease the size of cancer cells and their viability. It also reduces the levels of vascular endothelial growth factor (VEGF), cyclin D1, NAD⁺, and ATP, as well as cytochrome c oxidase activity in vitro. When tested in mice with induced breast cancer, carnosine proved to be non-toxic to healthy cells and exhibited chemopreventive activity by reducing tumor growth. Some evidence has also been reported at the clinical level. A randomized phase III prospective placebo-controlled trial showed the ability of Zn-carnosine to prevent dysphagia in breast cancer patients undergoing adjuvant radiotherapy. Despite this evidence, more preclinical and clinical studies are needed to better understand carnosine's anti-tumoral activity, especially in the context of breast cancer.

Keywords: breast cancer; carnosine; cell cycle; cell metabolism; cell proliferation; metastases.

Figure 1

Carnosine’s synthesis and metabolism occur through the activities of carnosine synthase 1 (CARNS1) and the carnosinases (carnosine dipeptidase 1 (CNDP1) and carnosine dipeptidase 2 (CNDP2), respectively). The tissues containing the highest levels of carnosine are represented. Created with https://smart.servier.com (accessed on 10 April 2023).

Figure 2

The percentage of patients affected by breast cancer who could develop metastases after diagnosis and primary tumor treatment is 20–30%. Breast cancer has demonstrated a metastatic propensity towards various organs, such as the bones (1st most targeted site, 75% of metastatic cases), lungs, liver, and brain. New approaches are available to investigate the molecular mechanism leading to metastatic heterogeneity, including genomic and transcriptomic analysis, single-cell sequencing strategies, and lineage tracing. Created with https://smart.servier.com (accessed on 10 April 2023).

Figure 3

Carnosine exerts its anti-tumoral activity by modulating the expression of genes and/or the secretion of factors related to tumor growth, including cell proliferation, apoptosis, and the cell cycle, as well as modulating the activities related to bioenergetics/cell energy metabolism. In particular, this dipeptide is able to modulate the expression and/or release of chemokines and cytokines (e.g., CCL2 and IL-1β), trophic factors (e.g., GM-CSF), and pro-inflammatory pathways (e.g., NF-κB), as well as the activities of different enzymes (e.g., IDH and MDX). Created with https://smart.servier.com (accessed on 10 April 2023).

Figure 4

Cytokines and chemokines playing a role in cancer development and progression. The left panel refers to the cytokines and chemokines positively regulated by the dipeptide carnosine. Created with https://smart.servier.com (accessed on 24 September 2023).