SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT

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dc.access.optionOpen Access
dc.contributor.advisorVan Dross-Anderson, Rukiyah
dc.contributor.authorLadin, Daniel A
dc.contributor.departmentPharmacology and Toxicology
dc.date.accessioned2018-01-23T13:40:59Z
dc.date.available2020-01-23T09:01:56Z
dc.date.created2017-08
dc.date.issued2017-08-16
dc.date.submittedAugust 2017
dc.date.updated2018-01-22T18:13:16Z
dc.degree.departmentPharmacology and Toxicology
dc.degree.disciplinePHD-Pharmacology - Toxicology
dc.degree.grantorEast Carolina University
dc.degree.levelDoctoral
dc.degree.namePh.D.
dc.description.abstractSkin cancers including non-melanoma skin cancer (NMSC) and melanoma are the most common form of cancer in the United States and thus represent a substantial burden to the health care system. Current chemotherapeutic treatments for skin cancer cause harmful side effects due to lack of tumor-cell selectivity. Our group previously found that the endocannabinoid, arachidonoyl-ethanolamide (AEA), induces apoptosis in tumor but not non-tumor cell lines through its metabolism to novel J-series prostaglandin-ethanolamides (prostamides). Therefore, the goal of this study was to synthesize the novel prostamide, 15-deoxy-[delta]¹²,¹⁴-prostamide J₂ (15d-PMJ₂) and determine the molecular mechanism of its antineoplastic activity. To our knowledge, we are the first group to successfully synthesize and biologically characterize a J-series prostamide. 15d-PMJ₂ exhibited potent and selective apoptotic properties in both non-melanoma and melanoma skin cancers. Furthermore, 15d-PMJ₂ was a potent inducer of tumor cell apoptosis in vivo. Induction of endoplasmic reticulum (ER) stress was required for 15d-PMJ₂ -mediated cancer cell death and was an important determinant of selective toxicity. This project also conducted a targeted structure-activity assessment of the electrophilic double bond, definitively showing this moiety as the molecular "warhead" necessary for the cytotoxic activity. Taken together, these data provide sound evidence that 15d-PMJ₂ may provide a clinical alternative for treatment of non-melanoma and melanoma skin cancer with less adverse effects.
dc.embargo.lift2019-08-01
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/10342/6490
dc.language.isoen
dc.publisherEast Carolina University
dc.subjectprostamide
dc.subjectcancer chemotherapy
dc.subjectprostaglandin ethanolamide
dc.subjectantineoplastic
dc.subjectanti-cancer therapeutic
dc.subjectmelanoma
dc.subjectnon-melanoma skin cancer
dc.subjectcell death
dc.subjectapoptosis
dc.subjectendoplasmic reticulum stress
dc.subject.meshAntineoplastic Agents
dc.subject.meshSkin Neoplasms
dc.subject.meshDermatologic Agents
dc.titleSYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT
dc.typeDoctoral Dissertation
dc.type.materialtext

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