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
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
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DOI：
10.1210/en.139.4.1972
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发表时间：
1998-04-01
期刊：
影响因子：
4.8
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Campbell, MJ;Park, S;Koeffler, HP
维生素D-3的类维生素A和类似物可以实现更大的体内应用，如果在可耐受剂量下遇到的毒副作用可以减轻。这些开环类固醇激素通常协同作用，因此，我们试图通过分离受体选择性类维生素A和有效的维生素D-3类似物[1 α，25（OH）（2）-16烯-23-炔-26，27，F-6- 19去甲-D-3，代号LH]的组合来剖析这些相互作用，使用一组代表逐渐更多转化表型的前列腺癌细胞系，我们发现LNCaP细胞系（转化最少）在其克隆生长中被LH和各种天然存在的和受体选择性的类维生素A相加或协同抑制，最有效的组合是与视黄酸受体（RAR）β γ-选择性类视色素（SR 11262）的组合。PC-3（中间转化）或DU-145（转化最多）均未发现该效应。我们还进行了RT-PCR来检查存在的RAR亚型，我们发现PC-3和DU-145不表达RAR β。RAR β在RAR β阴性PC-3细胞中的稳定表达导致对SR 11262和LH的敏感性增加，与RAR β表达量成正比。这项研究表明，RAR β可能在协同控制细胞增殖中起重要作用，并且随着前列腺癌细胞转化的增加而丧失表达。同时给予有效的维生素D-3类似物和受体选择性类维生素A可能具有治疗雄激素依赖性和非依赖性前列腺癌的治疗潜力。
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.