Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin

Abstract

We have synthesized and studied the ability of a series of seven novel 1 alpha,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 approximately 5 x 10(-11) M). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 approximately 2 x 10(-8) M). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

“…The same MTX treatment led to growth arrest, as measured by a complete block on cell proliferation (Figure 2A), and by the accumulation of the cellcycle inhibitor, p27/kip-1 ( Figure 2B, upper), whose upregulation correlates with growth arrest in LNCaP cells (Campbell et al, 1997). Methotrexate also promoted cellular differentiation, as measured by a significant rise in E-cadherin ( Figure 2B, middle), a marker of differentiation in the LNCaP cells (Campbell et al, 1997). The induction of the differentiation marker was MTX dosedependent ( Figure 2B, lower).…”

Meta-analysis of the Relation Between the VDR Gene TaqIpolymorphism and Genetic Susceptibility to Prostate Cancer in Asian Populations

“…The inhibitory protein can inhibit the activation of CCDK complexes, then the cells are arrested in G0/G1 phase; therefore, the proliferation of tumor cells is inhibited (Campbell et al, 1997;Ylikomi et al, 2002).…”

The vitamin D receptor in cancer

“…Following these studies antiproliferative effects have been demonstrated in a wide variety of cancer cell lines, including those from the prostate and breast (85)(86)(87)(88)(89)(90)(91)(92) . Thus, common models of VDR responses include MCF-7 breast cancer cells, LNCaP prostate cancer cells and CaCo2 colon cancer cells.…”