Campbell M J, Park S, Uskokovic M R, Dawson M I, Jong L, Koeffler H P
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.
Br J Cancer. 1999 Jan;79(1):101-7. doi: 10.1038/sj.bjc.6690018.
The secosteroid hormones, all-trans- and 9-cis-retinoic acid and vitamin D3, have demonstrated significant capacity to control proliferation in vitro of many solid tumour cell lines. Cooperative synergistic effects by these two ligands have been reported, and it is, therefore, possible that greater therapeutic effects could be achieved if these compounds were administered together. The role of retinoid-dependent anti-activator protein 1 (anti-AP-1) effects in controlling cancer cell proliferation appears significant. We have utilized an anti-AP-1 retinoid [2-(4,4-dimethyl-3,4-dihydro-2H-1 benzopyran-6-yl)carbonyl-2-(4-carboxyphenyl)-1,3,-dithiane; SR11238], which does not transactivate through a retinoic acid response element (RARE), and a potent vitamin D3 analogue [1alpha,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3, code name LH] together at low, physiologically safer doses against a panel of prostate cancer cell lines that represent progressively more transformed phenotypes. The LNCaP (least transformed) and PC-3 (intermediately transformed) cell lines were synergistically inhibited in their clonal growth by the combination of LH and SR11238, whereas SR11238 alone was essentially inactive. DU-145 cells (most transformed) were completely insensitive to these analogues. LNCaP cells, but neither PC-3 nor DU-145, underwent apoptosis in the presence of LH and SR11238. Transactivation of the human osteocalcin vitamin D response element (VDRE) by LH was not enhanced in the presence of SR11238, although the expression of E-cadherin in these cells was additively up-regulated in the presence of both compounds. These data suggest the anti-AP-1 retinoid and the vitamin D3 analogue may naturally act synergistically to control cell proliferation, a process that is interrupted during transformation, and that this combination may form the basis for treatment of some androgen-independent prostate cancer.
类维生素A激素、全反式视黄酸和9-顺式视黄酸以及维生素D3已显示出在体外控制多种实体瘤细胞系增殖的显著能力。已有报道称这两种配体具有协同增效作用，因此，如果将这些化合物联合给药，有可能获得更大的治疗效果。类维生素A依赖性抗激活蛋白1（抗AP-1）在控制癌细胞增殖中的作用似乎很重要。我们使用了一种抗AP-1类维生素A [2-(4,4-二甲基-3,4-二氢-2H-1-苯并吡喃-6-基)羰基-2-(4-羧基苯基)-1,3,-二硫杂环戊烷；SR11238]，它不会通过视黄酸反应元件（RARE）进行反式激活，以及一种强效维生素D3类似物[1α,25(OH)2-16-烯-23-炔-26,27-F6-19-去甲-D3，代号LH]，以低剂量、生理上更安全的剂量联合作用于一组代表逐渐更具转化表型的前列腺癌细胞系。LH和SR11238联合使用可协同抑制LNCaP（转化程度最低）和PC-3（中等转化）细胞系的克隆生长，而单独使用SR11238基本无活性。DU-145细胞（转化程度最高）对这些类似物完全不敏感。在LH和SR11238存在的情况下，LNCaP细胞会发生凋亡，但PC-3和DU-145细胞均不会。在SR11238存在的情况下，LH对人骨钙素维生素D反应元件（VDRE）的反式激活并未增强，尽管在两种化合物同时存在的情况下，这些细胞中E-钙黏蛋白的表达呈加性上调。这些数据表明，抗AP-1类维生素A和维生素D3类似物可能自然地协同作用以控制细胞增殖，这一过程在转化过程中被中断，并且这种联合可能构成治疗某些雄激素非依赖性前列腺癌的基础。
