Expression of retinoic acid receptor-β sensitizes prostate cancer cells to growth inhibition mediated by combinations of retinoids and a 19-nor hexafluoride vitamin D3 analog

被引:62
作者
Campbell, MJ
Park, S
Uskokovic, MR
Dawson, MI
Koeffler, HP
机构
[1] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Los Angeles Sch Med, Div Hematol Oncol, Los Angeles, CA 90048 USA
[2] SRI Int, Menlo Pk, CA 94025 USA
[3] Hoffmann La Roche Inc, Nutley, NJ 07110 USA
关键词
D O I
10.1210/en.139.4.1972
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Retinoids and analogs of vitamin D-3 may achieve greater in vivo applications if the toxic side effects encountered at pharmacologically active doses could be alleviated. These seco-steroid hormones often act in concert, and therefore, we attempted to dissect these interactions by isolating combinations of receptor-selective retinoids and a potent vitamin D-3 analog [1 alpha,25(OH)(2)-16ene-23-yne-26,27,F-6-19nor-D-3, code name LH] that were potent inhibitors of prostate cancer cell growth at low, physiologically safer doses. Using a panel of prostate cancer cell lines representing progressively more transformed phenotypes, we found that the LNCaP cell line (least transformed) was either additively or synergistically inhibited in its clonal growth by LH and various naturally occurring and receptor-selective retinoids, the most potent combination being with a retinoic acid receptor (RAR)beta gamma-selective retinoid (SR11262). The effect was not found with either PC-3 (intermediate transformation) or DU-145 (most transformed). We also undertook RT-PCR to examine the subtypes of RARs present, and we found that PC-3 and DU-145 did not express RAR beta. Stable expression of RAR beta into the RAR beta-negative PC-3 cells resulted in increased sensitivity to SR11262 and LH proportional to the amount of RAR beta expressed. This study indicates that RAR beta may play an important role in synergistically controlling cell proliferation, and expression is lost with increased prostate cancer cell transformation. Simultaneous administration of a potent vitamin D-3 analog and receptor-selective retinoids may have therapeutic potential for the treatment of androgen-dependent and -independent prostate cancer.
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页码:1972 / 1980
页数:9
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