SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-12 , 14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Daniel A Ladin (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

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 , ¹´-prostamide J‚‚ (15d-PMJ‚‚) 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-PMJ‚‚ exhibited potent and selective apoptotic properties in both non-melanoma and melanoma skin cancers. Furthermore , 15d-PMJ‚‚ was a potent inducer of tumor cell apoptosis in vivo. Induction of endoplasmic reticulum (ER) stress was required for 15d-PMJ‚‚ -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-PMJ‚‚ may provide a clinical alternative for treatment of non-melanoma and melanoma skin cancer with less adverse effects."

Additional Information

Publication

Dissertation

Language: English

Date: 2017

Keywords

prostamide, cancer chemotherapy, prostaglandin ethanolamide, antineoplastic, anti-cancer therapeutic, melanoma, non-melanoma skin cancer, cell death, apoptosis, endoplasmic reticulum stress

Subjects

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