title: QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells.
abstract: The enzyme 24-hydroxylase, also known as CYP24, metabolizes 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and is an established marker of vitamin D activity. Our studies evaluated the influence of a low-calcemic 1,25(OH)(2)D(3) analogue, QW-1624F2-2 (QW), on the regulation of CYP24 expression in MKL-4 cells, a metastatic mammary tumor cell model. 1,25(OH)(2)D(3) and its analogue, EB 1089, stimulated CYP24 induction at both protein and transcript levels. In contrast, QW failed to produce a sustained stimulation of CYP24, due, in large part, to a reduction in the stability of the CYP24 message. QW enhanced the capacity of 1,25(OH)(2)D(3) and EB 1089 to inhibit tumor cell proliferation by approximately 2-fold. QW also blocked the sustained induction of CYP24 expression by 1,25(OH)(2)D(3) and EB 1089, increased the potency of 1,25(OH)(2)D(3) and EB 1089, and inhibited breast tumor cell proliferation and invasion.
authors.affiliation: Department of Surgery, Dartmouth Medical School, One Medical Center Drive, HB 7850, Lebanon, NH 03756, USA. Sujatha.Sundaram@dartmouth.edu
authors.forename: Sujatha
authors.initials: S
authors.lastname: Sundaram
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Beckman
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wei
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Smith
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
authors.forename: David A
authors.initials: DA
authors.lastname: Gewirtz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D000970:Antineoplastic Agents; C113641:QW 1624F2-1; D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol