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

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

The Role of Tumor Inflammatory Microenvironment in Lung Cancer

“…Toshiko et al found that granatin A and granatin B, ellagitannins isolated from pomegranate leaves, and geraniin, their structural analog, could selectively suppress mPGES-1 expression without affecting COX-2 in non-small cell lung carcinoma A549 cells (Figure 5). The ellagitannins also downregulated TNF-α, inducible nitric oxide synthase, and antiapoptotic factor Bcl-2, and induced A549 cells to undergo apoptosis (Toda et al, 2020). Padwad et al found that berberine can induce dose-dependent resting and apoptosis of A549 cancer cells by regulating cyclin and inflammation independent of the mTOR pathway (Kumar et al, 2020).…”

Variation of the Polyphenolic Composition and Antioxidant Capacity of Freshly Prepared Pomegranate Leaf Infusions over One-Day Storage

“…Evidently, hydrolyzable tannins (HTs), another primary category of tannins has been also been proven to be abundant in PL extracts [ 16 , 25 , 26 ]. Both CTs and HTs in plants have reactive hydroxyl groups, thus, imparting free radical inhibitory activity to tannins.…”

“…have been extensively researched previously [ 15 , 35 , 36 ]. In the last decade, some studies reported the phytochemical screening and medicinal properties of the aqueous PL extracts mostly using laboratory water, such as distilled, deionized, or ultrapure grade water [ 15 , 25 , 37 , 38 , 39 ]; however, only some investigated the specific constituents. Orgil, et al [ 40 ] studied fresh PLs by extraction with cold distilled water and quantified the content of four bioactive compounds, including punicalagin, gallagic acid, ellagic acid, and gallic acid.…”

Autophagy in Gastric Mucosa: The Dual Role and Potential Therapeutic Target

“…NSAIDs are classic drugs to protect gastric mucosa, and the mechanism of their inhibition of COX enzyme has been widely known [ 74 ]. Recent studies have also found that gastric mucosa is affected through autophagy.…”