title: Synthesis and Evaluation of the Novel Prostamide, 15-Deoxy, Δ12,14-Prostamide J2, as a Selective Antitumor Therapeutic.
abstract: 15-deoxy, Δ12,14-prostaglandin J2-ethanolamide, also known as 15-deoxy, Δ12,14-prostamide J2(15d-PMJ2) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by COX-2. 15d-PMJ2preferentially 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-PMJ2cell death. 15d-PMJ2increased 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-PMJ2-mediated apoptosis, suggesting ER stress as a primary apoptotic mediator. Furthermore, the reactive double bond present within the cyclopentenone structure of 15d-PMJ2was identified as a required moiety for the induction of ER stress apoptosis. The effect of 15d-PMJ2on B16F10 melanoma growth was also evaluated by dosing C57BL/6 mice with 0.5 mg/kg 15d-PMJ2Tumors of animals treated with 15d-PMJ2exhibited 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-PMJ2-treated compared with control group animals. Taken together, these findings suggest that the novel prostamide, 15d-PMJ2, possesses potent antitumor activityin vitroandin vivoMol Cancer Ther; 16(5); 838-49. ©2017 AACR.
authors.affiliation: Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ladin
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt.
authors.forename: Eman
authors.initials: E
authors.lastname: Soliman
authors.affiliation: Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina.
authors.forename: Rene
authors.initials: R
authors.lastname: Escobedo
authors.affiliation: Department of Surgery, East Carolina University, Greenville, North Carolina.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Fitzgerald
authors.affiliation: Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Li V
authors.initials: LV
authors.lastname: Yang
authors.affiliation: Department of Chemistry, East Carolina University, Greenville, North Carolina.
authors.forename: Colin
authors.initials: C
authors.lastname: Burns
authors.affiliation: Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina. vandrossr@ecu.edu.|Center for Health Disparities, East Carolina University, Greenville, North Carolina.
authors.forename: Rukiyah
authors.initials: R
authors.lastname: Van Dross
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D051546:Cyclooxygenase 2; D015230:Prostaglandin D2; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C477819:15-deoxyprostaglandin J2; C497250:Ddit3 protein, mouse; C496540:PTGS2 protein, human