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

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    Author
    Ladin, Daniel A
    Abstract
    Skin 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.
    URI
    http://hdl.handle.net/10342/6490
    Subject
     prostamide; cancer chemotherapy; prostaglandin ethanolamide; antineoplastic; anti-cancer therapeutic; melanoma; non-melanoma skin cancer; cell death; apoptosis; endoplasmic reticulum stress 
    Date
    2017-08-16
    Citation:
    APA:
    Ladin, Daniel A. (August 2017). SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/6490.)

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    MLA:
    Ladin, Daniel A. SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT. Doctoral Dissertation. East Carolina University, August 2017. The Scholarship. http://hdl.handle.net/10342/6490. March 04, 2021.
    Chicago:
    Ladin, Daniel A, “SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT” (Doctoral Dissertation., East Carolina University, August 2017).
    AMA:
    Ladin, Daniel A. SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT [Doctoral Dissertation]. Greenville, NC: East Carolina University; August 2017.
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    • Dissertations
    • Pharmacology and Toxicology
    Publisher
    East Carolina University

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