title: ZK 156718, a low calcemic, antiproliferative, and prodifferentiating vitamin D analog.
abstract: The physiologically active form of vitamin D, 1,25-dihydroxyvitamin D(3), plays an important role not only in the establishment and maintenance of calcium metabolism, but also in regulating cell growth and differentiation. Because the clinical usefulness of 1,25-dihydroxyvitamin D(3) is limited by its tendency to cause hypercalcemia, new analogs with a better therapeutic profile have been synthesized, including ZK 156718. We compared the effects of 1,25-dihydroxyvitamin D(3) and ZK 156718 on growth, differentiation, and on p21(Waf1/Cip1) and p27(Kip1) expression in human colon cancer cells (Caco-2). Whereas ZK 156718 at the concentration [10(-8) M] was as potent as 10(-6) M 1,25-dihydroxyvitamin D(3) in inducing differentiation and p21(Waf1/Cip1) expression, it was even more effective in inhibiting cell growth and stimulating p27(Kip1) expression than 1,25-dihydroxyvitamin D(3) itself. In summary, our study presents a new and potent vitamin D analog with a decreased metabolic stability, making it useful for the treatment of a diversity of clinical disorders.
authors.affiliation: Division of Gastroenterology and Clinical Nutrition, Second Department of Internal Medicine, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gaschott
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Jürgen
authors.initials: J
authors.lastname: Stein
mesh_terms: D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002454:Cell Differentiation; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D008956:Models, Chemical; D017830:Octoxynol / Q000494:pharmacology; D011485:Protein Binding; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C493956:CDKN1A protein, human; D002120:Calcium Channel Agonists; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003902:Detergents; D025521:Tumor Suppressor Proteins; C447607:ZK 156718; D014807:Vitamin D; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017830:Octoxynol; D002117:Calcitriol; D002118:Calcium