SYNTHESIS AND MOLECULAR EVALUATION OF 15-DEOXY-Δ12,14-PROSTAMIDE J2 AS A NOVEL ANTI-SKIN CANCER AGENT
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Date
2017-08-16
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Authors
Ladin, Daniel A
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Publisher
East Carolina University
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.