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]¹²,¹4-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.

Additional Information

Publication

Dissertation

Language: English

Date: 2023

Subjects

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

Email this document to