Chemoprevention of upper aerodigestive tract cancer by dietary zinc

膳食锌对上呼吸消化道癌的化学预防

• 批准号: 7147917
• 负责人: LOUISE Y.Y. FONG
• 金额: $ 27.22万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147917
• 关键词: chemoprevention; neoplasm /cancer; zinc

DESCRIPTION (provided by applicant): Cancer of the upper aerodigestive tract (UADT), including esophageal and oral cancer, is a major cause of cancer deaths worldwide. In humans, dietary zinc deficiency is associated with an increased risk of esophageal and oral cancer. In rodents, zinc deprivation creates a precancerous condition in the UADT by causing increased cell proliferation and extensive gene expression changes, including upregulation of cyclooxygenase-2 (COX-2), an enzyme overexpressed in a variety of human premalignant and malignant lesions. Thus, zinc deficiency promotes UADT carcinogenesis by 4-nitroquinoline 1-oxide (NQO) and esophageal carcinogenesis by N-nitrosomethylbenzylamine (NMBA) in rodents. Zinc replenishment reverses cell proliferation, stimulates apoptosis, corrects COX-2 overexpression in esophageal epithelium, and inhibits carcinogenesis. We have obtained new data showing that (i) transcription factor NF-kappaB and COX-2 are co-overexpressed in zinc deficient (ZD) rat esophagi; (ii) zinc-deficient COX-2 null mice do not show the expected reduction in NMBA-induced tumor yield; and (iii) celecoxib, a COX-2 selective inhibitor, given singly to ZD rats formerly treated with NQO, is not as effective in tumor prevention as treatments that includes zinc. We propose that dietary zinc plays critical roles in UADT cancer initiation and chemoprevention and will examine the mechanisms whereby zinc affects these processes in vivo by the following interrelated AIMS: 1) to define the link between NF-kappaB and COX-2 induction in rat esophagus under in vivo zinc deficit by determining whether inhibitors targeting the kappaB kinase (IKK)/NF-kappaB activation pathway, including bortezomib, PS-1145, and NF-kappaB p65 small interfering (si)RNA are effective in knocking- down COX-2 expression. Effects on COX-2 expression, proliferation, and apoptosis will be compared with effects of zinc replenishment; 2) to determine the mechanism whereby zinc deficiency increases NMBA- induced forestomach carcinogenesis in COX-2 null mice, by investigating signals in arachidonic acid metabolism, independent of COX-2; 3) to investigate cancer prevention in the ZD rat UADT cancer model by evaluating efficacy and assessing biomarker modulating effects of zinc supplementation; zinc in combination with low doses of curcumin (inhibitor of NF-kappaB), zileuton (inhibitor of 5-LOX), and with low doses of dual treatment of inhibitors. A combination of zinc and low doses of inhibitors might be effective in prevention without the risk of the side effects associated with high doses of these agents. We will evaluate in lesions the localization of specific proliferation, apoptosis, and other relevant markers by immunohistochemistry. We will then use an appropriate subset of these markers as surrogate endpoints to assess the efficacy of each chemotherapeutic regimen. We will also compare gene expression changes caused by treatments with zinc or zinc plus inhibitors. The results of these studies will provide a new understanding of the role of dietary zinc in UADT carcinogenesis, as well as a basis for novel dietary approaches for the chemoprevention of these deadly cancers.

描述(申请人提供)：上呼吸道癌症(UADT)，包括食道癌和口腔癌，是全球癌症死亡的主要原因。在人类中，饮食缺锌与患食道癌和口腔癌的风险增加有关。在啮齿动物中，缺锌导致细胞增殖增加和广泛的基因表达变化，包括环氧合酶-2(COX-2)的上调，这是一种在各种人类癌前和恶性病变中过度表达的酶，从而导致UADT的癌前状态。因此，缺锌可促进4-硝基喹啉-1-氧化物(NQO)引起的UADT癌和N-亚硝基甲基苯甲胺(NMBA)引起的食道癌。补锌逆转细胞增殖，刺激细胞凋亡，纠正COX-2在食道上皮的过度表达，抑制癌变。我们已经获得了新的数据显示：(I)转录因子NF-kappaB和COX-2在缺锌(ZD)大鼠食道中过度表达；(Ii)缺锌COX-2基因缺失的小鼠没有显示出预期的NMBA诱导的肿瘤产量下降；以及(Iii)COX-2选择性抑制剂塞来昔布单独给予以前用过NQO治疗的ZD大鼠，在预防肿瘤方面不如包括锌的治疗有效。我们认为，膳食锌在UADT癌的启动和化学预防中起着关键作用，并将通过以下相互关联的目的在体内研究锌影响这些过程的机制：1)通过确定针对kappaB激酶(Ikk)/NF-kappaB激活途径的抑制剂(包括bortezomib、PS-1145和NF-kappaB p65小干扰(Si)RNA)是否有效地下调COX-2的表达，来确定体内缺锌条件下NF-kappaB和COX-2诱导的联系。为了研究锌缺乏对COX-2表达、增殖和细胞凋亡的影响，将与补锌效果进行比较；2)通过研究独立于COX-2的花生四烯酸代谢信号，确定缺锌可增加NMBA诱导的COX-2基因缺失小鼠前胃癌发生的机制；3)通过评估补锌的疗效和评估生物标记物的调节作用，研究补锌对ZD大鼠UADT癌症模型的预防作用；2)锌与低剂量姜黄素(核因子-kappaB的抑制剂)、齐留通(5-LOX的抑制剂)以及低剂量的双重治疗的联合治疗。锌和低剂量抑制剂的组合可能在预防方面有效，而不存在与高剂量这些药物相关的副作用风险。我们将通过免疫组织化学方法评估皮损中特异性增殖、凋亡和其他相关标志物的定位。然后，我们将使用这些标记物的适当子集作为替代终点来评估每种化疗方案的疗效。我们还将比较锌或锌加抑制剂处理引起的基因表达变化。这些研究的结果将提供对饮食锌在UADT致癌中作用的新的理解，以及为化学预防这些致命癌症的新的饮食方法提供基础。