Ellagitannins from Punica granatum leaves suppress microsomal prostaglandin E synthase-1 expression and induce lung cancer cells to undergo apoptosis

Biosci Biotechnol Biochem. 2020 Apr;84(4):757-763. doi: 10.1080/09168451.2019.1706442. Epub 2019 Dec 22.

Abstract

Prostaglandin E2 (PGE2), which is a potent pro-inflammatory lipid mediator, is biosynthesized from arachidonic acid by cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Non-steroidal anti-inflammatory drugs (NSAIDs) are used clinically as COX inhibitors, but they have gastrointestinal and cardiovascular side-effects. Thus, the terminal enzyme mPGES-1 holds promise as the next therapeutic target. In this study, we found that the ellagitannins granatin A and granatin B isolated from pomegranate leaves, and geraniin, which is their structural analog, selectively suppressed mPGES-1 expression without affecting COX-2 in non-small cell lung carcinoma A549 cells. The ellagitannins also down-regulated tumor necrosis factor α, inducible nitric oxide synthase, and anti-apoptotic factor B-cell chronic lymphocytic leukemia/lymphoma 2, and induced A549 cells to undergo apoptosis. These findings indicate that the ellagitannins have anti-inflammatory and anti-carcinogenic effects, due to their specific suppression of mPGES-1.Abbreviations: Bcl-2: B-cell chronic lymphocytic leukemia/lymphoma 2; COX: cyclooxygenase; CRE: cAMP response element; DHHDP: dehydrohexahydroxydiphenoyl; Et2O: diethyl ether; EtOAc: ethyl acetate; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; iNOS: inducible nitric oxide synthase; mPGES-1: microsomal prostaglandin E synthase-1; n-BuOH: water-saturated n-butanol; NSAIDs: non-steroidal anti-inflammatory drugs; NF-κB: nuclear factor-κB; PG: prostaglandin; TNF: tumor necrosis factor; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

Keywords: Microsomal prostaglandin E synthase-1; Punica granatum leaves; anti-inflammation; dehydrohexahydroxydiphenoyl group; lung cancer cells.

MeSH terms

  • A549 Cells
  • Apoptosis / drug effects*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Humans
  • Hydrolyzable Tannins / pharmacology*
  • Lung Neoplasms / pathology*
  • Plant Leaves / chemistry*
  • Pomegranate / chemistry*
  • Prostaglandin-E Synthases / antagonists & inhibitors*
  • Prostaglandin-E Synthases / genetics
  • Prostaglandin-E Synthases / metabolism
  • RNA, Messenger / genetics

Substances

  • Hydrolyzable Tannins
  • RNA, Messenger
  • Cyclooxygenase 2
  • PTGES protein, human
  • Prostaglandin-E Synthases