Synthesis and Evaluation of the Novel Prostamide, 15-Deoxy, Δ12,14-Prostamide J2, as a Selective Antitumor Therapeutic

Abstract

15-deoxy, Δ-prostaglandin J-ethanolamide, also known as 15-deoxy, Δ-prostamide J (15d-PMJ) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by COX-2. 15d-PMJ preferentially induced cell death and apoptosis in tumorigenic A431 keratinocytes and B16F10 melanoma cells compared with nontumorigenic HaCaT keratinocytes and Melan-A melanocytes. Activation of the ER stress execution proteins, PERK and CHOP10, was evaluated to determine whether this process was involved in 15d-PMJ cell death. 15d-PMJ increased the phosphorylation of PERK and expression of CHOP10 in tumorigenic but not nontumorigenic cells. The known ER stress inhibitors, salubrinal and 4-phenylbutaric acid, significantly inhibited 15d-PMJ-mediated apoptosis, suggesting ER stress as a primary apoptotic mediator. Furthermore, the reactive double bond present within the cyclopentenone structure of 15d-PMJ was identified as a required moiety for the induction of ER stress apoptosis. The effect of 15d-PMJ on B16F10 melanoma growth was also evaluated by dosing C57BL/6 mice with 0.5 mg/kg 15d-PMJ Tumors of animals treated with 15d-PMJ exhibited significantly reduced growth and mean weights compared with vehicle and untreated animals. TUNEL and IHC analysis of tumor tissues showed significant cell death and ER stress in tumors of 15d-PMJ-treated compared with control group animals. Taken together, these findings suggest that the novel prostamide, 15d-PMJ, possesses potent antitumor activity and.

Prostaglandins Isolated from the Octocoral Plexaura homomalla: In Silico and In Vitro Studies Against Different Enzymes of Cancer

“…This is the first time that these activities have been reported for this type of prostaglandins because the studies focus on anti-inflammatory activity. However, some studies have been found about cytotoxic effects of prostaglandin D (PGD), which is known as a homologous receptor of chemoattractants and especially PGD 2 -EA (prostaglandin-ethanolamide) and its catabolic product, 15-deoxy-∆ 12,14 -PGJ 2 -EA, which possess cytotoxic activity against skin cancer cells with a IC 50 of 18 µM and 20 µM respectively, concluding that these are potential therapeutic against skin cancer [14,15]. Showing in this way, that prostaglandins with hydroxyl groups and carboxylic acids have good characteristics as cytotoxic agents and that these can be potentially inhibitory against some types of cancer.…”

Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

“…However, proliferation rates in non-cancerous cells are typically low and as a consequence, these cells have minimal protein folding loads and ER stress levels. Hence, ER stress inducing agents cause death preferentially in cancer cells because the death threshold is more readily reached [10,13]. This selective tumor targeting often results in reduced adverse effects, a desired property for chemotherapeutic agents.…”

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

“…The metabolic products of AEA, prostamides-E 2 , F 2α , and -D 2 , do not bind to prostaglandin receptors, and they are metabolically stable relative to prostaglandins derived from arachidonic acid (Kozak et al, 2001 ; Matias et al, 2004 ). Recently, we demonstrated that AEA was also metabolized by COX-2 to novel J series prostamides that initiated tumor cell apoptosis (Kuc et al, 2012 ; Ladin et al, 2017 ). Because epithelial cancer cells typically overexpress COX-2, AEA was metabolized to pro-apoptotic J-series prostamides in tumor cells, but J-series prostamides were not detected in non-tumor cells which had low endogenous levels of COX-2 (Soliman et al, 2016 ).…”

“…Blockade of AEA degradation with the FAAH inhibitor, URB597, increased J-series prostaglandin synthesis and apoptosis; however, inhibition of CB1, CB2, and TRPV-1 receptors using selective antagonists did not reverse this effect (Soliman and Van Dross, 2016 ). Furthermore, cell treatment with exogenous 15-deoxy, Δ 12, 14 prostamide J 2 (15d-PMJ 2 ), the most abundant J-series product of AEA metabolism by COX-2, also caused cell death in vitro and in vivo (Ladin et al, 2017 ). Reports by Pastos et al also demonstrated that COX-2 was required to induce death in cancer cells treated with AEA (Patsos et al, 2005 , 2010 ).…”