title: Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines.
abstract: Dehydroepiandrosterone (DHEA) is a naturally occurring steroid synthesized in the adrenal cortex, gonads, brain, and gastrointestinal tract, and it is known to have chemopreventive and anti-proliferative actions on tumors. These effects are considered to be induced by the inhibition of glucose-6-phosphate dehydrogenase (G6PD) and/or HMG-CoA reductase (HMGR) activities. The present study was undertaken to investigate whether endogenous DHEA metabolites, i.e. DHEA-sulfate, 7-oxygenated DHEA derivatives, androsterone, epiandrosterone, and etiocholanolone, have anti-proliferative effects on cancer cells and to clarify which enzyme, G6PD or HMGR, is responsible for growth inhibition. Growth of Hep G2, Caco-2, and HT-29 cells, evaluated by 3-[4,5-dimethylthiazol]-2yl-2,5-diphenyl tetrazolium bromide (MTT) and bromodeoxyuridine incorporation assays, was time- and dose-dependently inhibited by addition of all DHEA-related steroids we tested. In particular, the growth inhibition due to etiocholanolone was considerably greater than that caused by DHEA in all cell lines. The suppression of growth of the incubated steroids was not correlated with the inhibition of G6PD (r=-0.031, n=9, NS) or HMGR (r=0.219, n=9, NS) activities. The addition of deoxyribonucleosides or mevalonolactone to the medium did not overcome the inhibition of growth induced by DHEA or etiocholanolone, while growth suppression by DHEA was partially prevented by the addition of ribonucleosides. These results demonstrate that endogenous DHEA metabolites also have an anti-proliferative action that is not induced by inhibiting G6PD or HMGR activity alone. These non-androgenic DHEA metabolites may serve as chemopreventive or anti-proliferative therapies.
authors.affiliation: Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Shigemasa
authors.initials: S
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Sugano
authors.initials: S
authors.lastname: Fukushima
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Aya
authors.initials: A
authors.lastname: Takagiwa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
mesh_terms: D002455:Cell Division / Q000187:drug effects*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005043:Etiocholanolone / Q000494:pharmacology; D005954:Glucosephosphate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010084:Oxidation-Reduction; D012263:Ribonucleosides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D012263:Ribonucleosides; D003687:Dehydroepiandrosterone; C003587:7-hydroxydehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005043:Etiocholanolone; D006903:Hydroxymethylglutaryl CoA Reductases; D005954:Glucosephosphate Dehydrogenase