No 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

Hyperproduced prostaglandin E2 by cyclooxygenase-2 and microsomal prostaglandin E synthase-1 evokes several pathophysiological responses such as inflammation and carcinogenesis. Our recent study demonstrated that Dioscorea japonica extract suppressed the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and induced apoptosis in lung carcinoma A549 cells. In the present study, we investigated the effects of Dioscorea japonica on squamous cell carcinoma of mouse skin. Dioscorea japonica feeding and Dioscorea japonica extract topical application suppressed the expression of cyclooxygenase-2, microsomal prostaglandin E synthase-1, interleukin-1β and interleukin-6 and inhibited tumor formation, hyperplasia and inflammatory cell infiltration. Immunohistochemical analyses showed the immunoreactivities of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in tumor keratinocytes and stronger immunoreactivities of cyclooxygenase-2 and hematopoietic prostaglandin D synthase in epidermal dendritic cells (Langerhans cells). Treatment with Dioscorea japonica decreased the immunoreactivity of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. These results indicate that Dioscorea japonica may have inhibitory effects on inflammation and carcinogenesis via suppression of the prostaglandin E2 synthetic pathway.