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Tumor Biology |
Division of Oncology/Hematology, Department of Medicine [Q. W., M. S. U., R. W.], and Department of Biochemistry and Molecular Biology [W. Y., S. C.], University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103
We investigated the capacity of 1,25-dihydroxyvitamin
D3 [1,25(OH)2D3] and
all-trans-retinoic acid (ATRA) to sensitize three breast
cancer cell lines to the cell killing effects of paclitaxel (Taxol) and
Adriamycin, two chemotherapeutic agents commonly used in the
treatment of breast cancer. In tissue culture colony assays,
1,25(OH)2D3 and ATRA were synergistic in
inhibiting the clonogenicity of MCF-7 and T-47D cells that expressed
estrogen receptor; vitamin D receptor; retinoic acid receptors (RARs)
, ß, and 
; and retinoid X receptors , ß, and but were
not additive in MDA-MB-231 cells that lacked expression of estrogen
receptor, RAR, and RARß. The hormones used individually or in
combination induced up to 40–50% cell death by a trypan blue
exclusion assay in a dose-dependent manner up to concentrations of
10-7 M in MCF-7 and T-47D cells, more modestly
in MDA-MB-231 cells, and not at all in MCF-10 and MCF-12 nontransformed
mammary epithelial cells. Pretreating the cancer cell lines with
1,25(OH)2D3 and ATRA individually or in
combination for 3 days prior to a 1-h incubation with paclitaxel or
Adriamycin decreased the ED50 for inhibition of colony
formation or for cell death by trypan blue by up to 2 logs for
paclitaxel and up to 1 log for Adriamycin in all three cell lines but
had no effect on chemotherapy-induced MCF-12 cell death. The effects of
the hormones were synergistic with those of the chemotherapy agents in
all of the breast cancer cell lines, generally at the higher
concentrations. Cell death took place by apoptosis. To determine one
potential reason for the greater potentiation of the effects of
paclitaxel than those of Adriamycin, we determined the effects of
preincubation of MCF-7 cells on paclitaxel-induced phosphorylation of
Bcl-2. Pretreatment of MCF-7 cells with either
1,25(OH)2D3 or ATRA increased the
phosphorylation of Bcl-2 by variable concentrations of paclitaxel.
These data suggest that pretreatment of breast cancer with
1,25(OH)2D3 or ATRA lowers the threshold for
cell killing by chemotherapy agents and may provide a novel treatment
option for this disease.
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