CAROTENOID/RETINOID MODULATION OF CELLULAR REDOX STATUS AND CANCER

类胡萝卜素/类维生素A调节细胞氧化还原状态和癌症

• 批准号: 6293840
• 负责人: JOHN EDGAR FRENCH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6293840
• 关键词: acetylcysteine; antioxidants; apoptosis; benzopyrenes; biological signal transduction; carcinogenesis inhibitor; carotenoids; chemical carcinogenesis; cysteine; dietary supplements; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; lymphoma; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplastic process; nutrient interaction; nutrition aspect of cancer; nutrition related tag; oxidation reduction reaction; retinoids; skin neoplasms

Both N-acetyl cysteine (NAC) and 4-hydroxyphenylretinamide (4- HPR) were found to have significant effects on the multiplicity of TPA-induced papillogenesis in male TG.AC mice. 4 -HPR was found to inhibit papillogenesis and the inhibition was only observed if present early in papillogenesis. Follow- up experiments demonstrate that 4-hpr is anti-inflammatory in the early hours after initial TPA treatment. We are evaluating the possibility that 4-HPR stimulates apoptosis of inflammatory cells. It appears from two separate experiments that when fed on top of a soy- based semi-purified diet, NAC at 1.5% and 3.0% of the diet stimulates the multiplicity of these papillomas. This is most interesting because NAC is usually inhibitory to the carcinogenic process- we have identified a paradoxical activity of this antioxidant. This phenomenon does not occur when NAC is fed in casein-based diets. Thus, it appears there is an interaction between NAC and some component(s) of the soy isolate (not occurring in the casein-based diet) which cooperate to cause the increased papilloma multiplicity. A second objective is to test the hypothesis that the modulation of dietary antioxidants at two distinctly different stages of pathogenesis will have opposite effects on the eventual yield of malignant tumor formation. We postulate that minimizing oxidative stress (by dietary antioxidants) in the earliest stages (promotion) of tumor pathogenesis will serve to functionally neutralize the inflammatory component of tumor promotion, thereby eventually translating to a decreased yield of malignant tumors. In contrast, we anticipate that minimizing oxidative stress (thus inhibiting apoptosis) specifically in the period when induced lesions progress from preneoplasia through malignancy will result in a selective advantage for the damaged cells and eventually yield more malignancies. We therefore evaluated this hypothesis using Tg.AC x p53 haploinsufficient mice treated topically with B(a)P to induce skin carcinogenesis. Compared to control diets, NAC feeding was associated with a lower tumor burden (multiplicity) of tumors but stimulated it stimulated their progression to malignancies. Finally, a serendipitous observation from this skin cancer experiment was that NAC feeding was associated with enhanced early deaths, possibly from lymphomas. We have begun an in vivo investigation to confirm and amplify this observation. An analogous investigation in vitro shows that NAC supplementation to mitogen treated splenocytes stimulates proliferation and inhibits apoptosis. Thus we have identified three contexts where the prototypic antioxidant exacerbated tumor progression.

N-乙酰半胱氨酸(NAC)和4-羟基苯基视黄胺(4- HPR)被发现对 TPA诱导雄性TG.AC小鼠乳头形成的多样性。 4-HPR可抑制乳头状突起及其抑制作用 只有在乳头形成的早期才能观察到。以下为- UP实验表明，4-HPR具有抗炎作用。 最初的TPA治疗后的早期几个小时。我们正在评估 4-羟色胺受体刺激细胞凋亡的可能性 炎性细胞。它似乎来自两个不同的实验 当以大豆为基础的半纯饮食喂养时，NAC 在1.5%和3.0%的饲料中，刺激了 这些乳头状瘤。这是最有趣的，因为NAC是 通常对致癌过程有抑制作用-我们有 发现了这种抗氧化剂自相矛盾的活性。这 在以酪蛋白为基础的NAC中喂食时不会出现这种现象 节食。因此，NAC之间似乎存在一种互动 和大豆分离的某些成分(S)(不存在于 以酪蛋白为基础的饮食)，这些合作导致增加 乳头状瘤多发性。第二个目标是测试 假设饮食中抗氧化剂的调节作用在两个 明显不同的发病阶段会有相反的情况 对恶性肿瘤形成的最终产率的影响。我们 假设将氧化压力降至最低(通过饮食 抗氧化剂)在肿瘤的早期阶段(促进) 发病机制将在功能上中和 促进肿瘤的炎性成分，从而最终 转化为降低了恶性肿瘤的产量。在……里面 相比之下，我们预计将氧化应激降至最低(因此 抑制细胞凋亡)特别是在诱导期间 病变从良性病变到恶性病变的进展 从而对受损细胞产生选择性优势 最终会产生更多的恶性肿瘤。因此我们评估了 这一假设使用了Tg.AC x p53单倍体缺陷小鼠 用B(A)P局部治疗以诱发皮肤癌。 与对照饮食相比，NAC喂养与 降低肿瘤的负担(多发性)，但刺激它 刺激了他们的恶变。最后，一个 从皮肤癌实验中偶然观察到 NAC喂养与早期死亡增加有关， 可能是淋巴瘤造成的。我们已经开始了一个活体实验 进行调查以证实和放大这一观察结果。一个 体外相似研究表明，NAC 补充有丝分裂原处理的脾细胞刺激 增殖并抑制细胞凋亡。因此，我们已经确定 三种情况下原型抗氧化剂加剧 肿瘤进展。