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: 7894618
• 负责人: LOUISE Y.Y. FONG
• 金额: $ 27.3万
• 依托单位: THOMAS JEFFERSON 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894618
• 关键词: Adverse effects; Affect; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Biological Markers; Bortezomib; Cancer Etiology; Cancer Model; Carcinoma; Cell Proliferation; Cessation of life; Chemoprevention; Curcumin; Cytosolic Phospholipase A2; Data; Dietary Zinc; Dose; Enzymes; Epithelium; Esophageal; Esophagus; Gene Expression; Genes; Human; Hyperplasia; Immunohistochemistry; Knockout Mice; Lesion; Leukotrienes; Link; Malignant - descriptor; Malignant Neoplasms; Membrane; Metabolism; Mus; NF-kappa B; Neoplasms; Nitroquinolines; Oligonucleotides; Oral; Oxides; Pathway interactions; Phospholipids; Phosphotransferases; Play; Precancerous Conditions; Premalignant; Prevention; Process; Rattus; Regimen; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Supplementation; Surrogate Endpoint; Testing; Tissues; Up-Regulation; Upper aerodigestive tract cancer; Velcade; Zileuton; Zinc; Zinc deficiency; base; cancer initiation; cancer prevention; carcinogenesis; celecoxib; cyclooxygenase 2; deprivation; in vivo; inhibitor/antagonist; kinase inhibitor; knock-down; malignant mouth neoplasm; multicatalytic endopeptidase complex; nitrosobenzylmethylamine; novel; overexpression; p65; prevent; transcription factor; tumor

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（由申请人提供）：上呼吸消化道癌症（UADT），包括食管癌和口腔癌，是全球癌症死亡的主要原因。在人类中，饮食锌缺乏与食管癌和口腔癌的风险增加有关。在啮齿类动物中，缺锌通过引起细胞增殖增加和广泛的基因表达变化，包括环氧化酶-2（考克斯-2）（一种在多种人类癌前病变和恶性病变中过表达的酶）上调，在UADT中产生癌前状态。因此，锌缺乏促进UADT致癌作用的4-硝基喹啉1-氧化物（NQO）和食管癌的N-亚硝基甲基苄胺（NMBA）在啮齿动物。补充锌可逆转细胞增殖，刺激细胞凋亡，纠正食管上皮中考克斯-2的过度表达，并抑制癌变。我们已经获得了新的数据，表明（i）转录因子NF-κ B和考克斯-2在缺锌（ZD）大鼠食管中共过表达;（ii）缺锌考克斯-2缺失小鼠没有显示出预期的NMBA诱导的肿瘤产量的减少;和（iii）塞来昔布，一种考克斯-2选择性抑制剂，单独给予先前用NQO处理的ZD大鼠，在预防肿瘤方面不如含锌治疗有效。我们提出，膳食锌在UADT癌症的发生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来研究锌在体内影响这些过程的机制：1）通过确定靶向kappaB激酶（IKK）/NF-κ B活化途径的抑制剂，包括硼替佐米，PS-1145和NF-κ B p65小干扰（si）RNA有效敲低考克斯-2表达。将对考克斯-2表达、增殖和细胞凋亡的影响与锌补充的影响进行比较; 2）通过研究花生四烯酸代谢中的信号（不依赖于考克斯-2）来确定锌缺乏增加考克斯-2缺失小鼠中NMBA诱导的前胃癌发生的机制; 3）通过评价功效和评估锌补充的生物标志物调节作用来研究ZD大鼠UADT癌症模型中的癌症预防;锌与低剂量姜黄素（NF-κ B抑制剂）、齐留通（5-LOX抑制剂）的组合，以及与低剂量的抑制剂双重治疗的组合。锌和低剂量抑制剂的组合可能有效地预防，而没有与高剂量这些药物相关的副作用的风险。我们将通过免疫组化评估病变中特异性增殖、凋亡和其他相关标志物的定位。然后，我们将使用这些标志物的适当子集作为替代终点，以评估每种化疗方案的疗效。我们还将比较锌或锌加抑制剂治疗引起的基因表达变化。这些研究的结果将为膳食锌在UADT致癌作用中的作用提供新的认识，并为这些致命癌症的化学预防提供新的膳食方法的基础。