title: Gemini vitamin D analogues inhibit estrogen receptor-positive and estrogen receptor-negative mammary tumorigenesis without hypercalcemic toxicity.
abstract: Numerous preclinical, epidemiologic, and clinical studies have suggested the benefits of vitamin D and its analogues for the prevention and treatment of cancer. However, the hypercalcemic effects have limited the use of 1alpha,25(OH)(2)D(3), the hormonally active form of vitamin D. To identify vitamin D analogues with better efficacy and low toxicity, we have tested >60 novel Gemini vitamin D analogues with a unique structure of two side chains for growth inhibition of breast cancer cells. Our initial studies found that some Gemini analogues are 5-15 times more active than 1alpha,25(OH)(2)D(3) in growth inhibition assay. In vivo experiments were designed to study the inhibitory effect of selected Gemini vitamin D analogues against mammary carcinogenesis by using (a) an N-methyl-N-nitrosourea-induced estrogen receptor (ER)-positive mammary tumor model and (b) an MCF10DCIS.com xenograft model of ER-negative mammary tumors. Among vitamin D analogues we tested, Gemini 0072 [1alpha,25-dihydroxy-20S-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] and Gemini 0097 [1alpha,25-dihydroxy-20R-21(3-trideuteromethyl-3-hydroxy-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-19-nor-cholecalciferol] administration inhibited by 60% the NMU-induced mammary tumor burden compared with the NMU-treated control group, but these compounds were devoid of hypercalcemia toxicity. In an ER-negative xenograft model, Gemini 0097 significantly suppressed tumor growth without hypercalcemia toxicity. We found that the inhibitory effect of Gemini 0097 was associated with an increased level of cyclin-dependent kinase inhibitor p21 and the insulin-like growth factor binding protein 3 in both ER-positive and ER-negative mammary tumors. Our results suggest that Gemini vitamin D analogues may be potent agents for the prevention and treatment of both ER-positive and ER-negative breast cancer without hypercalcemia toxicity.
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Lee
authors.forename: Shiby
authors.initials: S
authors.lastname: Paul
authors.forename: Nadi
authors.initials: N
authors.lastname: Atalla
authors.forename: Paul E
authors.initials: PE
authors.lastname: Thomas
authors.forename: Xinjie
authors.initials: X
authors.lastname: Lin
authors.forename: Ill
authors.initials: I
authors.lastname: Yang
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Xi
authors.initials: X
authors.lastname: Zheng
authors.forename: You-Rong
authors.initials: YR
authors.lastname: Lou
authors.forename: Allan H
authors.initials: AH
authors.lastname: Conney
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000453:epidemiology / Q000209:etiology / Q000517:prevention & control; D015994:Incidence; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008770:Methylnitrosourea; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C411462:1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3); D011960:Receptors, Estrogen; D008770:Methylnitrosourea; D002117:Calcitriol