Palmitoylethanolamide Reduces Colon Cancer Cell Proliferation and Migration, Influences Tumor Cell Cycle and Exerts In Vivo Chemopreventive Effects.

Ester Pagano,Raffaele Capasso,Donatella Cicia,Angelo A Izzo,Francesca Borrelli,Tommaso Venneri,M Francesca Nanì,Barbara Romano,Giuseppe Lucariello,Vincenzo Brancaleone,Nunzio A Cacciola

doi:10.3390/cancers13081923

Abstract

Simple SummaryTreatment of colon cancer remains a significant unmet need. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide also present in food sources. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. Here, we found that ultramicronized PEA inhibited tumor cell proliferation mediated by PPAR-α and GPR55, induced cell cycle arrest in the G2/M phase and DNA fragmentation, reduced cell migration and exerted beneficial effects in the azoxymethane model of colonic tumors. Collectively, these data provide evidence on the beneficial effects of PEA in colon carcinogenesis.Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the endocannabinoid anandamide. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. We deepened this aspect by studying the effects of PEA (ultramicronized PEA, um-PEA) on colon cancer cell proliferation, migration and cell cycle as well as its effects in a murine model of colon cancer. Results showed that um-PEA inhibited tumor cell proliferation via peroxisome proliferator-activated receptor α and G protein-coupled receptor 55, induced cell cycle arrest in the G2/M phase, possibly through cyclin B1/CDK1 upregulation, and induced DNA fragmentation. Furthermore, um-PEA reduced tumor cell migration by reducing MMP2 and TIMP1 expression. In vivo administration of um-PEA exerted beneficial effects in the azoxymethane model of colonic tumors, by reducing the number of preneoplastic lesions and tumors. Collectively, our findings provide novel proofs on the effects of um-PEA in colon carcinogenesis.

Highlights

This article is an open access articleColorectal cancer (CRC) is one of the leading causes of cancer-related death, with a rate of incidence that is remarkably increasing worldwide [1]
In order to depict the potential role of PEA in intestinal carcinogenesis, we initially tested whether ultamicronized PEA treatment was able to modify any colorectal cancer cell function in vitro
By using the BrdU incorporation assay, we tested the antiproliferative effect of ultamicronized PEA (um-PEA) on tumor HCT116 cells

Summary

Introduction

Colorectal cancer (CRC) is one of the leading causes of cancer-related death, with a rate of incidence that is remarkably increasing worldwide [1]. CRC has been placed at the second position in the oncologic death ranking for European countries in 2018 [3]. Factors include lifestyle, diet, genetic factors, alterations in gut microbiota, a history of inflammatory bowel disease (IBD) and other additional pathologies (e.g., diabetes, obesity). Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the family of acylethanolamides (NAEs), which includes anandamide (AEA) and oleoylethanolamide (OEA). PEA exerts anti-inflammatory, analgesic and neuroprotective properties with a multitarget mechanism, mostly mediated by peroxisome proliferatoractivated receptor α (PPAR-α) [4]

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