Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer.

Abstract

Docosahexaenoic acid (DHA) is known to inhibit breast cancer in the rat. Here we investigated whether DHA itself or select metabolites can account for its antitumor action. We focused on metabolites derived from the lipoxygenase (LOX) pathway since we previously showed that they were superior anti-proliferating agents compared to DHA; 4-OXO-DHA was the most potent. A lipidomics approach detected several LOX-metabolites in plasma and the mammary gland in rats fed DHA; we also identified for the first time, 4-OXO-DHA in rat plasma. In a reporter assay, 4-OXO-DHA and 4-HDHA were more effective activators of PPARɣ than DHA. In breast cancer cell lines, 4-OXO-DHA induced PPARɣ and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) but inhibited the activity of NF-κB and suppressed PI3K and mTOR signaling. Because of the structural characteristics of 4-OXO-DHA (Michael acceptor), not shared by any of the other hydroxylated-DHA, we used MS and showed that it can covalently modify the cysteine residue of NF-κB. We have also shown that the chemopreventive effect of DHA is associated with significant reduction of PGE2 levels, in both rat mammary tumors induced by MNU and non-involved mammary tissues. Collectively, our results indicate that 4-OXO-DHA is the metabolite of choice in future chemoprevention studies.

• Authors: Kun-Ming Chen, Henry Thompson, John P Vanden-Heuvel, Yuan-Wan Sun, Neil Trushin, Cesar Aliaga, Krishne Gowda, Shantu Amin, Bruce Stanley, Andrea Manni, Karam El-Bayoumy
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 410 (01 11 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33431978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Antineoplastic Agents
• Lipids
• PPAR gamma
• Docosahexaenoic Acids
• Lipoxygenase
• Dinoprostone

Topics

• Animals
• Anticarcinogenic Agents (metabolism, therapeutic use)
• Antineoplastic Agents (isolation & purification, metabolism, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Catalysis
• Dinoprostone (metabolism)
• Docosahexaenoic Acids (metabolism)
• Female
• Lipid Metabolism (physiology)
• Lipids (analysis)
• Lipoxygenase (metabolism)
• Metabolic Networks and Pathways (physiology)
• PPAR gamma (metabolism)
• Rats
• Rats, Sprague-Dawley