Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway

We have shown previously that 1 alpha, 25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D-3 (Gemini) compounds, which have two side chains attached to carbon-20, had increased anti-tumor activities against breast, prostate and leukemia cell lines in comparison to 1,25(OH)(2) vitamin D-3. This prompted us to synthesize additional Gemini compounds with further modifications and evaluate their anticancer effects. Most effective in this series was 1,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-vitamin D-3 [Gemini-23-yne-26,27-hexafluoro-D-3]. This analog was approximately 10-fold more potent than previously characterized Gemini compounds in inhibiting the clonal growth of HL-60, MCF-7 and LNCaP cell lines. Also in MCF-7 cells, Gemini-23-yne-26,27-hexafluoro-D-3 caused dephosphorylation of the oncogenic kinase, Akt, resulting in dephosphorylation of the Akt target proteins, Forkhead transcription factor and mammalian target of rapamycin (mTOR). Downstream effectors of mTOR were also inhibited by the analog as demonstrated by decreased phosphorylation of both S6 kinase, and the translation inhibitor, 4E-BPI. The mTOR pathway regulates mRNA translation; exposure of MCF-7 cells to Gemini-23-yne-26,27-hexafluoro-D-3 decreased their rate of protein synthesis and increased the association of 4E-BP1 with the translation initiation factor, eIF4E. Inhibtion of the Akt-mTOR pathway represents a novel mechanism by which vitamin D-3 analogs may modulate the expression and activity of proteins involved in cancer cell proliferation. (c) 2006 Elsevier Ltd. All rights reserved.