title: Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells.
abstract: Inflammation is a cancer hallmark that underlies cancer incidence and promotion, and eventually progression to metastasis. Therefore, adding an anti-inflammatory drug to standard cancer regiments may improve patient outcome. One such drug, aspirin (acetylsalicylic acid, ASA), has been explored for cancer chemoprevention and anti-tumor activity. Besides inhibiting the cyclooxygenase 2-prostaglandin axis, ASA's anti-cancer activities have also been attributed to nuclear factor ĸB (NFĸB) inhibition. Because prolonged ASA use may cause gastrointestinal toxicity, a prodrug strategy has been implemented successfully. In this prodrug design the carboxylic acid of ASA is masked and additional pharmacophores are incorporated. This protocol describes how we synthesized an aspirin-fumarate prodrug, GTCpFE, and characterized its inhibition of the NFĸB pathway in breast cancer cells and attenuation of the cancer stem-like properties, an important NFĸB-dependent phenotype. GTCpFE effectively inhibits the NFĸB pathway in breast cancer cell lines whereas ASA lacks any inhibitory activity, indicating that adding fumarate to ASA structure significantly contributes to its activity. In addition, GTCpFE shows significant anti-cancer stem cell activity by blocking mammosphere formation and attenuating the cancer stem cell associated CD44+CD24-immunophenotype. These results establish a viable strategy to develop improved anti-inflammatory drugs for chemoprevention and cancer therapy.
authors.affiliation: Physiology and Biophysics, College of Medicine, University of Illinois at Chicago; ikastr2@uic.edu.
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.affiliation: Medicinal Chemistry and Pharmacognosy, College of Medicine, University of Illinois at Chicago.
authors.forename: Loruhama
authors.initials: L
authors.lastname: Delgado-Rivera
authors.affiliation: College of Pharmacy, University of Illinois at Chicago.
authors.forename: Gergana
authors.initials: G
authors.lastname: Georgieva
authors.affiliation: Medicinal Chemistry and Pharmacognosy, College of Medicine, University of Illinois at Chicago.
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
authors.affiliation: Physiology and Biophysics, College of Medicine, University of Illinois at Chicago.
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D005650:Fumarates / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005650:Fumarates; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011355:Prodrugs; D001241:Aspirin