Jinno H, Steiner M G, Mehta R G, Osborne M P, Telang N T
Division of Carcinogenesis and Prevention, Strang Cancer Research Laboratory, The Rockefeller University, New York, NY 10021, USA.
Carcinogenesis. 1999 Feb;20(2):229-36. doi: 10.1093/carcin/20.2.229.
Epithelial cells from non-cancerous mammary tissue in response to exposure to chemical carcinogens or transfection with oncogenes exhibit hyperproliferation and hyperplasia prior to the development of cancer. Aberrant proliferation may, therefore, represent a modifiable early occurring preneoplastic event that is susceptible to chemoprevention of carcinogenesis. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR), has exhibited preventive efficacy in several in vitro and in vivo breast cancer models, and represents a promising chemopreventive compound for clinical trials. Clinically relevant biochemical and cellular mechanisms responsible for the chemopreventive effects of HPR, however, are not fully understood. Experiments were performed on preneoplastic human mammary epithelial 184-B5/HER cells derived from reduction mammoplasty and initiated for tumorigenic transformation by overexpression of HER-2/neu oncogene, to examine whether HPR inhibits aberrant proliferation of these cells and to identify the possible mechanism(s) responsible for the inhibitory effects of HPR. Continuous 7-day treatment with HPR produced a dose-dependent, reversible growth inhibition. Long-term (21 day) treatment of 184-B5/HER cells with HPR inhibited anchorage-dependent colony formation by approximately 80% (P < 0.01) relative to that observed in the solvent control. A 24 h treatment with cytostatic 400 nM HPR produced a 25% increase (P = 0.01) in G0/G1 phase, and a 36% decrease (P = 0.01) in S phase of the cell cycle. HPR treatment also induced a 10-fold increase (P = 0.02) in the sub-G0 (apoptotic) peak that was down-regulated in the presence of the antioxidant N-acetyl-L-cysteine. Treatment with HPR resulted in a 30% reduction of cellular immunoreactivity to tyrosine kinase, whereas immunoreactivity to p185HER remained essentially unaltered. HPR exposure resulted in time-dependent increase in cellular metabolism of the retinoid as evidenced by increased formation of the inert metabolite N-(4-methoxyphenyl)-retinamide (MPR) and progressive increase in apoptosis. Thus, HPR-induced inhibition of aberrant proliferation may be caused, in part, by its ability to inhibit HER-2/neu-mediated proliferative signal transduction, retard cell cycle progression and upregulate cellular apoptosis.
来自非癌性乳腺组织的上皮细胞在接触化学致癌物或用癌基因转染后，在癌症发生之前会出现过度增殖和增生。因此，异常增殖可能代表一种可改变的早期肿瘤前事件，易受化学致癌预防的影响。合成类视黄醇N-(4-羟基苯基)视黄酰胺（HPR）在几种体外和体内乳腺癌模型中已显示出预防效果，是一种有前途的用于临床试验的化学预防化合物。然而，HPR化学预防作用的临床相关生化和细胞机制尚未完全了解。对来自缩乳术的肿瘤前人类乳腺上皮184-B5/HER细胞进行实验，并通过HER-2/neu癌基因的过表达启动致瘤转化，以检查HPR是否抑制这些细胞的异常增殖，并确定HPR抑制作用的可能机制。用HPR连续7天治疗产生了剂量依赖性、可逆的生长抑制。相对于溶剂对照，用HPR对184-B5/HER细胞进行长期（21天）治疗可使锚定依赖性集落形成抑制约80%（P<0.01）。用400 nM的细胞生长抑制剂HPR处理24小时，使细胞周期的G0/G1期增加25%（P=0.01），S期减少36%（P=0.01）。HPR处理还使亚G0（凋亡）峰增加了10倍（P=0.02），在抗氧化剂N-乙酰-L-半胱氨酸存在下该峰下调。用HPR处理导致细胞对酪氨酸激酶的免疫反应性降低30%，而对p185HER的免疫反应性基本保持不变。HPR暴露导致类视黄醇的细胞代谢随时间增加，这表现为惰性代谢物N-(4-甲氧基苯基)视黄酰胺（MPR）形成增加以及凋亡逐渐增加。因此，HPR诱导的异常增殖抑制可能部分是由于其抑制HER-2/neu介导的增殖信号转导、延缓细胞周期进程和上调细胞凋亡的能力。
