Xu Hui, Cheepala Satish, McCauley Elisabeth, Coombes Kevin, Xiao Lianchun, Fischer Susan M, Clifford John L
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center-Shreveport and the Feist-Weiller Cancer Center, Shreveport, Louisiana 17730, USA.
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):969-79. doi: 10.1158/1078-0432.CCR-05-1648.
Fenretinide [N-(4-hydroxyphenyl)retinamide or 4-HPR] is a synthetic retinoid analogue with antitumor and chemopreventive activities. N-(4-Methoxyphenyl)retinamide (4-MPR) is the most abundant metabolite of 4-HPR detected in human serum following 4-HPR therapy. We have shown in in vitro studies that 4-HPR and 4-MPR can act independent of the classic nuclear retinoid receptor pathway and that 4-HPR, but not 4-MPR, can also activate nuclear retinoid receptors. In this study, we have compared the chemopreventive effects of topically applied 4-HPR and 4-MPR with the primary biologically active retinoid, all-trans retinoic acid (ATRA), in vivo in the mouse skin two-stage chemical carcinogenesis model. All three retinoids suppressed tumor formation but the effect of 4-HPR and 4-MPR, and not of ATRA, was sustained after their discontinuation. The tumor-suppressive effects of 4-HPR and 4-MPR were quantitatively and qualitatively similar, suggesting that the two may be acting through the same retinoid receptor-independent mechanism(s). We further explored this effect in vitro by analyzing primary cultures of mouse keratinocytes treated with the same retinoids. All three could induce apoptosis with a 48-hour treatment and only ATRA and 4-HPR induced an accumulation of cells in the G1 phase of the cell cycle. This finding is consistent with our previous results showing that the effects of phenylretinamides on the cell cycle are retinoid receptor dependent whereas apoptosis induction is not. A microarray-based comparison of gene expression profiles for mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and TPA + 4-HPR or TPA + 4-MPR reveals a high degree of coincidence between the genes regulated by the two phenylretinamides. We propose that 4-HPR may exert therapeutic and chemopreventive effects by acting primarily through a retinoid receptor-independent mechanism(s) and that 4-MPR may contribute to the therapeutic effect of 4-HPR by acting through the same retinoid receptor-independent mechanism(s).
芬维A胺[N-(4-羟基苯基)视黄酰胺或4-HPR]是一种具有抗肿瘤和化学预防活性的合成类视黄醇类似物。N-(4-甲氧基苯基)视黄酰胺(4-MPR)是4-HPR治疗后在人血清中检测到的最主要代谢产物。我们在体外研究中表明，4-HPR和4-MPR可以独立于经典的核类视黄醇受体途径发挥作用，并且4-HPR可以激活核类视黄醇受体，而4-MPR则不能。在本研究中，我们在小鼠皮肤两阶段化学致癌模型中，比较了局部应用4-HPR和4-MPR与主要生物活性类视黄醇全反式维甲酸(ATRA)的化学预防效果。所有三种类视黄醇都能抑制肿瘤形成，但在停药后，4-HPR和4-MPR的效果持续存在，而ATRA则不然。4-HPR和4-MPR的肿瘤抑制作用在数量和质量上相似，这表明两者可能通过相同的不依赖类视黄醇受体的机制发挥作用。我们通过分析用相同类视黄醇处理的小鼠角质形成细胞原代培养物，在体外进一步探究了这种作用。所有三种在处理48小时后都能诱导细胞凋亡，只有ATRA和4-HPR能诱导细胞周期G1期细胞的积累。这一发现与我们之前的结果一致，即苯基视黄酰胺对细胞周期的作用依赖于类视黄醇受体，而诱导细胞凋亡则不然。基于微阵列对单独用12-O-十四酰佛波醇-13-乙酸酯(TPA)处理以及TPA + 4-HPR或TPA + 4-MPR处理的小鼠皮肤基因表达谱的比较显示，两种苯基视黄酰胺调节的基因之间存在高度一致性。我们提出，4-HPR可能主要通过不依赖类视黄醇受体的机制发挥治疗和化学预防作用，而4-MPR可能通过相同的不依赖类视黄醇受体的机制对4-HPR的治疗效果有贡献。
