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Synergistic inhibition of prostate cancer cell lines by a 19- nor hexafluoride vitamin D3 analogue and anti-activator protein 1 retinoid

By M J Campbell, S Park, M R Uskokovic, M I Dawson, L Jong and H P Koeffler

Abstract

The secosteroid hormones, all- trans- and 9- cis -retinoic acid and vitamin D3, have demonstrated significant capacity to control proliferation in itro of many solid tumour cell lines. Cooperative synergistic effects by these two ligands have been reported, and it is, therefore, possible that greater therapeutic effects could be achieved if these compounds were administered together. The role of retinoid-dependent anti-activator protein 1 (anti-AP-1) effects in controlling cancer cell proliferation appears significant. We have utilized an anti- AP-1 retinoid [2-(4,4-dimethyl-3,4-dihydro-2H-1 benzopyran-6-yl)carbonyl-2-(4-carboxyphenyl)-1,3,-dithiane; SR11238], which does not transactivate through a retinoic acid response element (RARE), and a potent vitamin D3analogue [1α,25(OH)2-16-ene-23-yne-26,27-F6-19-nor -D3, code name LH] together at low, physiologically safer doses against a panel of prostate cancer cell lines that represent progressively more transformed phenotypes. The LNCaP (least transformed) and PC-3 (intermediately transformed) cell lines were synergistically inhibited in their clonal growth by the combination of LH and SR11238, whereas SR11238 alone was essentially inactive. DU-145 cells (most transformed) were completely insensitive to these analogues. LNCaP cells, but neither PC-3 nor DU-145, underwent apoptosis in the presence of LH and SR11238. Transactivation of the human osteocalcin vitamin D response element (VDRE) by LH was not enhanced in the presence of SR11238, although the expression of E-cadherin in these cells was additively up-regulated in the presence of both compounds. These data suggest the anti-AP-1 retinoid and the vitamin D3 analogue may naturally act synergistically to control cell proliferation, a process that is interrupted during transformation, and that this combination may form the basis for treatment of some androgen-independent prostate cancer. © 1999 Cancer Research Campaig

Topics: Regular Article
Publisher: Nature Publishing Group
OAI identifier: oai:pubmedcentral.nih.gov:2362165
Provided by: PubMed Central
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    1. (1995). Chromosone 5 suppresses tumorigenicity of PC3 prostate cancer cells: correlation with re-expression of a-catenin and restoration of E-cadherin function.
    2. (1996). Detection of apoptosis and cell proliferation.
    3. (1992). Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 52: 5104–5109 Umbas
    4. (1994). Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.
    5. (1994). Suppression of squamous cell carcinoma growth and differentiation by retinoids.
    6. (1995). Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of the NFATp/AP-1 complex formation by a nuclear hormone receptor.

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