Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type-Independent Effect

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Abstract
The ability of a number of prostaglandin F2α(PGF2α) analogs to mobilize intracellular Ca2+ [Ca2+]i and to compete for [3H]PGF2α binding to prostaglandin F2α receptors (FP) was evaluated. Radioligand binding studies measuring displacement of [3H]PGF2αby a variety of FP prostaglandin analogs yielded the following rank order of affinities: travoprost acid [(+)-16-m-trifluorophenoxy tetranor PGF2α; (+)-fluprostenol] > bimatoprost acid (17-phenyl-trinor PGF2α) ≫ unoprostone (13,14-dihydro-15-keto-20-ethyl PGF2α) = bimatoprost (17-phenyl-trinor PGF2α ethyl amide) ≥ Lumigan (bimatoprost ophthalmic solution). In FP functional studies, travoprost acid (EC50 = 17.5–37 nM, n = 13), bimatoprost acid (EC50 = 23.3–49.0 nM,n = 6–12), unoprostone (EC50 = 306-1270 nM, n = 4–8), bimatoprost (EC50 = 3070- 3940 nM, n = 4–9), and Lumigan (EC50 = 1470–3190 nM,n = 5–9) concentration dependently stimulated [Ca2+]i mobilization via the rat (A7r5 cells), mouse (3T3 cells), and cloned human ocular FP prostanoid receptors. The rank order of potency of these compounds at the FP receptor of the three species was similar and in good agreement with the determined binding affinities. The agonist effects of these compounds were concentration dependently blocked by the FP receptor-selective antagonist, AL-8810 (11β-fluoro-15-epi-15-indanyl-tetranor PGF2α) (Ki = 0.6–1.3 μM). These studies have demonstrated that bimatoprost, unoprostone, and bimatoprost acid possess direct agonist activities at the rat, mouse, and human FP prostanoid receptor and that travoprost acid is the most potent of the synthetic FP prostaglandin analogs tested.