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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2427-2433
NEOPLASIA
Novel vitamin D3 analog,
21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates
cell growth, differentiation, apoptosis, cell cycle, and induction
of PTEN in leukemic cells
Jun-ichi Hisatake,
James O'Kelly,
Milan R. Uskokovic,
Shigeru Tomoyasu, and
H. Phillip Koeffler
From the Division of Hematology/Oncology, Cedars-Sinai
Medical Center, UCLA School of Medicine, Los Angeles, CA; Hoffmann
LaRoche, Nutley, NJ; and Department of Hematology, Showa University
School of Medicine, Tokyo, Japan.
The active form of vitamin D3,
1,25(OH)2D3, inhibits proliferation and induces
differentiation of a variety of malignant cells. A new class of vitamin
D3 analogs, having 2 identical side chains attached to
carbon-20, was synthesized and the anticancer effects evaluated. Four
analogs were evaluated for their ability to inhibit growth of myeloid
leukemia (NB4, HL-60), breast (MCF-7), and prostate (LNCaP) cancer
cells. All 4 analogs inhibited growth in a dose-dependent manner. Most
effective was 21-(3-methyl-3-hydroxy-butyl)-19-nor D3
(Gemini-19-nor), which has 2 side chains and removal of the C-19.
Gemini-19-nor was approximately 40 625-, 70-, 23-, and 380-fold more
potent than 1,25(OH)2D3 in inhibiting 50%
clonal growth (ED50) of NB4, HL-60, MCF-7, and LNCaP cells,
respectively. Gemini-19-nor (10 8 M) strongly induced
expression of CD11b and CD14 on HL-60 cells (90%); in contrast,
1,25(OH)2D3 (108 M) stimulated
only 50% expression. Annexin V assay showed that Gemini-19-nor and
1,25(OH)2D3 induced apoptosis in a
dose-dependent fashion. Gemini-19-nor (108 M, 4 days)
caused apoptosis in approximately 20% of cells, whereas 1,25(OH)2D3 at the same concentration did not
induce apoptosis. Gemini-19-nor increased in HL-60 both the proportion
of cells in the G1/G0 phase and expression
level of p27kip1. Moreover, Gemini-19-nor
stimulated expression of the potential tumor suppressor, PTEN.
Furthermore, other inducers of differentiation, all-trans-retinoic acid and 12-O-tetradecanoylphorbol
13-acetate, increased PTEN expression in HL-60. In summary,
Gemini-19-nor strongly inhibited clonal proliferation in various types
of cancer cells, especially NB4 cells, suggesting that further studies
to explore its anticancer potential are warranted. In addition, PTEN expression appears to parallel terminal differentiation of myeloid cells.
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