Synthesis And Evaluation Of The Novel Prostamide, 15-Deoxy, Delta(12,14)-Prostamide J(2), As A Selective Antitumor Therapeutic

15-deoxy, Delta(12,14)-prostaglandin J(2)-ethanolamide, also known as 15-deoxy, Delta(12,14)-prostamide J(2) (15d-PMJ(2)) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by COX-2. 15d-PMJ(2) 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(2) cell death. 15d-PMJ(2) 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(2)-mediated apoptosis, suggesting ER stress as a primary apoptotic mediator. Furthermore, the reactive double bond present within the cyclopentenone structure of 15d-PMJ(2) was identified as a required moiety for the induction of ER stress apoptosis. The effect of 15d-PMJ(2) on B16F10 melanoma growth was also evaluated by dosing C57BL/6 mice with 0.5 mg/kg 15d-PMJ(2). Tumors of animals treated with 15d-PMJ(2) 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(2)-treated compared with control group animals. Taken together, these findings suggest that the novel prostamide, 15d-PMJ(2), possesses potent antitumor activity in vitro and in vivo. (C) 2017 AACR.