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

Abstract

The secosteroid hormones, all- trans - and 9- cis -retinoic acid and vitamin D 3 , 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 D 3 analogue [1α,25(OH) 2 -16-ene-23-yne-26,27-F 6 -19- nor -D 3 , 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 D 3 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 Campaign

Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells

“…Simultaneously, p27/Kip 1, an inhibitor of cyclin-dependent kinases whose upregulation correlates with growth-arrest, was increased at the protein level up to 3.4 times as shown by Western blotting ( Figure 1B). Furthermore, R1881 treatment resulted in a more than two-fold rise in E-cadherin protein expression ( Figure 1C), a generally-accepted indicator of differentiation in LNCaP cells (Campbell et al, 1999). higher PpIX accumulation in androgen-pretreated cells than in proliferating control cells (13 experiments, two dishes/experiment).…”

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

“…We, and others, have previously identi®ed hexa¯uoride analogs, such as 1a,25-(OH)2-16-ene-23-yne-26,27-hexa¯uoride-19-nor-D 3 (LH), as being highly potent in a diverse range of cancer cell types, largely as a result of its ability to resist CYP24-mediated metabolism Koike et al, 1997;Evans et al, 1999;Munker et al, 1996;Anzano et al, 1994). Furthermore we have investigated ways to enhance the antiproliferative potency of these, and other, analogs for example, by combination with retionids (Campbell et al, 1998(Campbell et al, , 1999b. However few if any of these strategies demonstrated potent action against all cell lines especially the highly recalcitrant, androgenindependent DU-145.…”

Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer

“…Some nuclear receptors, including RAR-␣, negatively regulate AP-1 activity by down-regulating c-fos. A synthetic retinoid, SR11238, with predominately anti-AP-1 activity and minimal ability to transactivate through a retinoic acid response element (RARE), synergistically inhibited the growth of both the androgen-responsive prostate cancer cell line LNCaP as well as the androgenindependent cell line PC-3 in combination with a Vitamin D analog [45]. Transactivation of the osteocalcin Vitamin D response element (VDRE) by the Vitamin D analog was not enhanced by SR11238, but the expression of E-cadherin was additively upregulated by both compounds.…”