Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma
Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma
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DOI：
10.1093/jnci/93.7.516
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发表时间：
2001-04-04
影响因子：
10.3
通讯作者：
Benbrook, DM
中科院分区：
文献类型：
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作者：
Guruswamy, S;Lighfoot, S;Benbrook, DM
背景：维甲酸类似物，称为类维生素A，在预防乳腺癌和卵巢癌的临床试验中显示出希望。经典的类维生素A与调节细胞生长的视黄酸受体结合。一些新的类维生素A，如芬维A胺，即，N-（4-羟苯基）维A酰胺（4-HPR），通过视黄酸受体独立的机制诱导细胞凋亡，然而，他们似乎只有在浓度高于临床化学预防试验中达到的水平才能做到这一点。在较低浓度（小于或等于1 μ M）下，4-HPR通过受体依赖性机制诱导分化，其作用类似于经典的类维生素A。我们的目标是比较新的受体非依赖性（凋亡）类维生素A与经典的生长抑制类维生素A在临床上可实现的剂量对卵巢组织的生长，分化和凋亡的影响。研究方法：四种受体非依赖性（凋亡）和七种生长抑制性类维生素A，包括合成的低毒性化合物称为heteroarotinoids，以1 μ M的浓度给予卵巢原代和癌细胞系的器官型培养物：OVCAR-3，Caov-3和SK-OV-3。固定、包埋和切片后，通过测量增殖标记物Ki-67/myb的表达来定量生长分数，通过粘蛋白的表达来评估分化，并且通过TUNEL测定来评估凋亡。对数据进行斯皮尔曼相关分析，所有P值均为双侧。结果：所有11种维甲酸逆转了所有肿瘤培养物中与癌表型相关的特征。在类维生素A处理的OVCAR-3和Caov-3培养物中始终观察到腺体结构，但在未处理的OVCAR-3和Caov-3培养物中未观察到腺体结构。所有维甲酸降低生长分数，和一些增加粘蛋白的表达。所有受体非依赖性类维生素A和两种受体依赖性类维生素A均诱导细胞凋亡，且诱导作用与粘蛋白MUC 1表达增加显著相关（r =.83; P =.03）。具有酯连接基团的类维生素A不诱导细胞凋亡，但与MUC 1诱导作用相关，降低了生长分数（r =-0.93; P =.02）。结论：在临床可达到的浓度下，所有测试的类维生素A降低生长分数，诱导分化和凋亡，MUC 1表达的诱导与作用机制有关。
Background: Retinoic acid analogues, called retinoids, have shown promise in clinical trials in preventing breast and ovarian cancers. Classic retinoids bind to retinoic acid receptors, which regulate cell growth. Some novel retinoids, such as fenretinide, i.e., N-(4-hydroxyphenyl)retinamide (4-HPR), induce apoptosis through retinoic acid receptor-independent mechanisms; however, they appear to do so only at concentrations above those achieved in clinical chemoprevention trials. At lower concentrations (less than or equal to1 muM), 4-HPR acts like classic retinoids, by inducing differentiation through a receptor-dependent mechanism. Our goal was to compare the effects of novel receptor-independent (apoptotic) retinoids with those of classic growth-inhibitory retinoids at clinically achievable doses on growth, differentiation, and apoptosis in ovarian tissue. Methods: Four receptor-independent (apoptotic) and seven growth-inhibitory retinoids, including synthetic, low-toxicity compounds called heteroarotinoids, were administered at concentrations of 1 muM to organotypic cultures of ovarian primary and cancer cell lines: OVCAR-3, Caov-3, and SK-OV-3. After fixation, embedding, and sectioning, the growth fraction was quantified by measuring expression of the proliferation marker Ki-67/myb, differentiation was assessed by expression of mucin, and apoptosis was evaluated by the TUNEL assay. Spearman correlation analysis was performed on the data, and all P values were two-sided. Results: All 11 retinoids reversed characteristics associated with the cancerous phenotype in all neoplastic cultures. Glandular structures were observed consistently in retinoid-treated, but not in untreated, OVCAR-3 and Caov-3 cultures. All retinoids decreased growth fractions, and some increased mucin expression. All receptor-independent retinoids and two receptor-dependent retinoids induced apoptosis, and the induction correlated significantly with increased expression of the mucin MUC1 (r =.83; P =.03), Retinoids with ester-linking groups did not induce apoptosis but decreased the growth fraction in correlation with MUC1 induction (r = -.93; P =.02). Conclusions: At clinically achievable concentrations, all retinoids tested decrease the growth fraction, induce differentiation and apoptosis, Induction of MUC1 expression is implicated in the mechanisms of action.