A novel bioactive derivative of eicosapentaenoic acid (EPA) suppresses intestinal tumor development in ApcΔ14/+ mice

Abstract

Familial adenomatous polyposis (FAP) is a genetic disorder characterized by the development of hundreds of polyps throughout the colon. Without prophylactic colectomy, most individuals with FAP develop colorectal cancer at an early age. Treatment with EPA in the free fatty acid form (EPA-FFA) has been shown to reduce polyp burden in FAP patients. Since high-purity EPA-FFA is subject to rapid oxidation, a stable form of EPA compound has been developed in the form of magnesium l-lysinate bis-eicosapentaenoate (TP-252). We assessed the chemopreventive efficacy of TP-252 on intestinal tumor formation using ApcΔ14/+ mice and compared it with EPA-FFA. TP-252 was supplemented in a modified AIN-93G diet at 1, 2 or 4% and EPA-FFA at 2.5% by weight and administered to mice for 11 weeks. We found that administration of TP-252 significantly reduced tumor number and size in the small intestine and colon in a dose-related manner and as effectively as EPA-FFA. To gain further insight into the cancer protection afforded to the colon, we performed a comprehensive lipidomic analysis of total fatty acid composition and eicosanoid metabolites. Treatment with TP-252 significantly decreased the levels of arachidonic acid (AA) and increased EPA concentrations within the colonic mucosa. Furthermore, a classification and regression tree (CART) analysis revealed that a subset of fatty acids, including EPA and docosahexaenoic acid (DHA), and their downstream metabolites, including PGE3 and 14-hydroxy-docosahexaenoic acid (HDoHE), were strongly associated with antineoplastic activity. These results indicate that TP-252 warrants further clinical development as a potential strategy for delaying colectomy in adolescent FAP patients.

Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

“…Another lipid-related metabolite, HDoHE, was also negatively correlated with tumor weight, in line with a previous study that revealed a higher level of HDoHE was associated with smaller CRC tumors in mice, owing to the anti-inflammatory properties of HDoHE [39]. These findings indicate that ZEA may aggravate tumor growth by interfering with systemic metabolism.…”

“…We observed that serum hydroxyeicosatetraenoic acids (HETE) level was lower in the ZEA group, potentially leading to defects in PPARγ activation which is responsible for apoptosis in CRC [46]. Another lipid-related metabolite, hydroxydocosahexaenoic acid (HDoHE), was also found to be negatively correlated with tumor weight, in line with a previous study that revealed that a higher level of HDoHE was associated with smaller CRC tumors in mice due to the anti-inflammatory property of HDoHE [47]. These results suggested that ZEA could possibly hinder the production of anti-inflammatory metabolites, leading to aggravated tumor growth.…”

“…We observed that serum HETE level was lower in the ZEA group, potentially leading to defects in peroxisome proliferator-activated receptor γ activation, which is responsible for apoptosis in CRC [38]. Another lipid-related metabolite, HDoHE, was also negatively correlated with tumor weight, in line with a previous study that revealed a higher level of HDoHE was associated with smaller CRC tumors in mice, owing to the anti-inflammatory properties of HDoHE [39]. These findings indicate that ZEA may aggravate tumor growth by interfering with systemic metabolism.…”

Omega-3 PUFA Loaded in Resveratrol-Based Solid Lipid Nanoparticles: Physicochemical Properties and Antineoplastic Activities in Human Colorectal Cancer Cells In Vitro

“…In addition, only after the encapsulation, DHA was efficiently retroconverted into EPA. The increased efficiency of cancer cells to incorporate EPA after administration of the SLN containing either its precursor LNA or its metabolic product DHA seems to be of great interest, since several reports have demonstrated the ability of EPA or its derivatives to exert a protective action in animals and patients at high risk for CRC [ 56 , 57 , 58 , 59 ]. Particularly, the possibility of efficiently increasing (by almost three folds) the content of EPA in colonic cells by administering LNA-RV-SLN seems particularly noteworthy, since the direct intake of EPA from fish or after its purification is much less sustainable and affordable than the use of LNA for encapsulation, being this metabolic precursor of EPA largely found in vegetables and seeds.…”

<p>Nanomedicine-based formulations containing &omega;-3 polyunsaturated fatty acids: potential application in cardiovascular and neoplastic diseases</p>

“…This implies that the encapsulation of either DHA or ALA into RV-based SLN could also markedly increase the CRC content of EPA, which, according to several recent reports, seems to protect against CRC risk better than all the other main ω-3 PUFAs. [106][107][108] The more efficient conversion of SLN-encapsulated ALA is particularly interesting when considering that ALA is present at high levels in a variety of seeds and vegetables, and its increased intake could be achieved more easily and in a more sustainable way compared to an increased consumption of EPA itself.…”