Guo W X, Gill P S, Antakly T
Department of Pathology, University of Montreal, Quebec, Canada.
Cancer Res. 1995 Feb 15;55(4):823-9.
Retinoids, a group of natural and synthetic vitamin A analogues the receptors of which belong to the superfamily of steroid receptors, can exert profound effects on growth and/or differentiation of embryonic and neoplastic cells. Kaposi's sarcoma (KS), previously a rare multicentric neoplasm, has become epidemic with HIV infection, although the etiology of KS remains obscure. In the present study, the effects of two potent retinoids, all-trans-retinoic acid (RA) and 13-cis-RA, on the expression of retinoic acid receptor alpha and the growth of AIDS-related KS (AIDS-KS) cells were examined. The proliferation of AIDS-KS cells was significantly inhibited by RA and 13-cis-RA in a dose-dependent manner with 50% inhibitory concentration of 1.4 x 10(-10) M and 4.7 x 10(-9) M, respectively, which correlate with their potency. Growth inhibition was time dependent with maximal inhibition of 90% after 3 days of treatment with 10(-8) M RA. Growth inhibition by RA was further potentiated by forskolin (1 microM), an intracellular cyclic AMP-inducing agent. Moreover, RA treatment blocked the proliferative effect of oncostatin M and tumor necrosis factor alpha, two major KS autocrine growth factors. The effects of RA were accompanied by a dramatic increase in nuclear staining for retinoic acid receptor alpha and in the relative number of strongly positive retinoic acid receptor alpha nuclei. Finally, RA induced morphological changes as KS cells became more flattened, better spread, and more adhesive to the substrate. These results suggest that retinoids inhibit proliferation of AIDS-KS cells and further support their utility as therapeutic agents in AIDS-KS.
维甲酸是一组天然和合成的维生素A类似物，其受体属于类固醇受体超家族，可对胚胎细胞和肿瘤细胞的生长和/或分化产生深远影响。卡波西肉瘤（KS）以前是一种罕见的多中心肿瘤，随着HIV感染而变得流行，尽管KS的病因仍不清楚。在本研究中，检测了两种强效维甲酸，全反式维甲酸（RA）和13-顺式维甲酸，对维甲酸受体α表达和艾滋病相关卡波西肉瘤（AIDS-KS）细胞生长的影响。RA和13-顺式维甲酸以剂量依赖方式显著抑制AIDS-KS细胞的增殖，其50%抑制浓度分别为1.4×10^(-10) M和4.7×10^(-9) M，这与其效力相关。生长抑制是时间依赖性的，用10^(-8) M RA处理3天后最大抑制率为90%。细胞内环磷酸腺苷诱导剂福斯可林（1 microM）进一步增强了RA对生长的抑制作用。此外，RA处理阻断了抑瘤素M和肿瘤坏死因子α这两种主要的KS自分泌生长因子的增殖作用。RA的作用伴随着维甲酸受体α核染色的显著增加以及强阳性维甲酸受体α核相对数量的增加。最后，RA诱导形态学变化，KS细胞变得更扁平、铺展更好且对底物的粘附性更强。这些结果表明维甲酸抑制AIDS-KS细胞的增殖，并进一步支持其作为AIDS-KS治疗药物的效用。
