PMID- 16777406
OWN - NLM
STAT- MEDLINE
DCOM- 20061106
LR  - 20211203
IS  - 0960-0760 (Print)
IS  - 0960-0760 (Linking)
VI  - 100
IP  - 4-5
DP  - 2006 Aug
TI  - Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the 
      Akt/mTOR signaling pathway.
PG  - 107-16
AB  - We have shown previously that 1alpha, 
      25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D3 (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 D3. 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 
      D3 [Gemini-23-yne-26,27-hexafluoro-D3]. 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-D3 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-BP1. The 
      mTOR pathway regulates mRNA translation; exposure of MCF-7 cells to 
      Gemini-23-yne-26,27-hexafluoro-D3 decreased their rate of protein synthesis and 
      increased the association of 4EBP-1 with the translation initiation factor, 
      eIF4E. Inhibition of the Akt-mTOR pathway represents a novel mechanism by which 
      vitamin D3 analogs may modulate the expression and activity of proteins involved 
      in cancer cell proliferation.
FAU - O'Kelly, James
AU  - O'Kelly J
AD  - Division of Hematology/Oncology, Cedars Sinai Medical Center, UCLA School of 
      Medicine, Los Angeles, CA, USA. okellyj@cshs.org
FAU - Uskokovic, Milan
AU  - Uskokovic M
FAU - Lemp, Nathan
AU  - Lemp N
FAU - Vadgama, Jay
AU  - Vadgama J
FAU - Koeffler, H Phillip
AU  - Koeffler HP
LA  - eng
GR  - CA042710/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20060614
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 0 
      (1,25-dihydroxy-20S-21(3-hydroxy-3-methyl-butyl)-23-yne-26,27-hexafluoro-vitamin 
      D3)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Phosphoproteins)
RN  - 1C6V77QF41 (Cholecalciferol)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/metabolism
MH  - Animals
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Cell Cycle/drug effects
MH  - Cell Cycle Proteins
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cholecalciferol/*analogs & derivatives/chemical synthesis/chemistry/pharmacology
MH  - Eukaryotic Initiation Factor-4E/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Molecular Structure
MH  - Neoplasms/metabolism/pathology
MH  - Phosphoproteins/metabolism
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/06/17 09:00
MHDA- 2006/11/07 09:00
CRDT- 2006/06/17 09:00
PHST- 2006/01/09 00:00 [received]
PHST- 2006/04/24 00:00 [accepted]
PHST- 2006/06/17 09:00 [pubmed]
PHST- 2006/11/07 09:00 [medline]
PHST- 2006/06/17 09:00 [entrez]
AID - S0960-0760(06)00135-X [pii]
AID - 10.1016/j.jsbmb.2006.04.003 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):107-16. doi: 
      10.1016/j.jsbmb.2006.04.003. Epub 2006 Jun 14.