Role of adenosine A3 receptor in suppressing prostate cancer

腺苷A3受体在抑制前列腺癌中的作用

• 批准号: 7516278
• 负责人: Vickram Ramkumar
• 金额: $ 21.83万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-13 至 2011-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516278
• 关键词: ADORA3 gene; Adenosine; Adenosine A3 Receptor; Adverse effects; Agonist; Androgens; Animals; Antifungal Agents; Antineoplastic Agents; Applications Grants; Cell Proliferation; Cells; Cessation of life; Chemicals; Class; Complement Factor B; Conjugated Estrogens; Count; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Disease regression; Dose; Drug usage; Estrogens; Extracellular Signal Regulated Kinases; Frequencies; Gelatinase A; Gelatinase B; Gene Expression; Generations; Goals; Human Cell Line; Injection of therapeutic agent; Intraperitoneal Injections; Ketoconazole; Kidney Failure; Laboratories; Left; Lesion; Localized; Lung; Malignant neoplasm of prostate; Mediating; Membrane; Metastatic Prostate Cancer; Metastatic to; Methods; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Mitogens; N(6)-(3-iodobenzyl)-5' -N-methylcarboxamidoadenosine; NADPH Oxidase; Neoplasm Metastasis; Nuclear; Nucleosides; Numbers; Oxides; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Platinum; Process; Proteins; Public Health; Rattus; Reactive Oxygen Species; Regulation; Research; Role; SCID Mice; Schedule; Severe Combined Immunodeficiency; Signal Pathway; Source; Superoxides; System; Testing; Time; Transcription Factor AP-1; Treatment Effectiveness; Treatment Protocols; Vascular Endothelial Growth Factors; Week; Withdrawal; base; cancer cell; cell motility; chemotherapeutic agent; cytochrome b558; day; docetaxel; enzyme activity; hearing impairment; human CYBA protein; immunodeficient mouse model; intravenous injection; link protein; migration; mortality; novel; protein expression; transcription factor; tumor

DESCRIPTION (provided by applicant): Prostate cancer metastasis is a serious sequelae of prostate cancer, associated with increased mortality and reduces treatment effectiveness. Androgen withdrawal therapy, the hallmark of treatment promotes tumor regression. However, treatment benefits wane after an average of 18-24 months, necessitating the use of second-line agents. Chemotherapeutic agents though effective, are not curative and there is an urgent need for novel therapies to be initiated early in the course of the disease. Our laboratory has recently shown that activation of the adenosine A3 receptor (A3AR) subtype inhibits prostate cancer cell proliferation and metastasis in rat and human cell lines of androgen-independent metastatic prostate cancer and in SCID mice injected with the AT6.1 rat metastatic prostate cancer line. The "metastatic phenotype" is mediated in part through the generation of high levels of ROS by these cells via the NADPH oxidase system, which activates signaling pathways, such as nuclear factor (NF)-:B and extracellular signal regulated kinase (ERK) mitogen activated protein (MAP) kinase/activator protein (AP-1) transcription factor. Through these mechanisms, ROS positively regulates the expression of proteins linked to the metastatic phenotype. In this proposal, we will test the hypothesis that activation of the A3AR inhibits the NADPH oxidase activity and thereby suppresses downstream signaling pathways, primarily ERK1/2 MAP kinase and NF-:B and metastatic gene expression regulated by ROS. In a severe combined immunodeficient (SCID) mouse model, we will determine the optimal A3AR treatment protocol to effect maximum inhibition of metastasis. The specific goals are: (1) To determine the optimal treatment parameters for using A3AR agonist to reduce prostate cancer metastasis, focusing on optimal doses and treatment schedules and also determining whether these agonists are effective following establishment of cell metastasis. (2) To determine the mechanism(s) by which the A3AR inhibits ROS generation and motility and metastasis of prostate cancer cells. We will focus on NADPH oxidase and determine the mechanism(s) underlying its activation and subunit expression via the ERK1/2 MAP kinase/AP-1 and NF-:B pathways. Overall, these studies will provide novel information concerning the efficacy of and mechanism underlying the anti-metastatic actions of A3AR agonists in prostate cancer and provide a rational basis for using this class of drug clinically. PUBLIC HEALTH RELEVANCE: Prostate cancer metastasis is a serious consequence of prostate cancer, which if left untreated, could result in death. Several treatment options exist, such as androgen withdrawal therapy and the use of drugs such as ketoconazole and Premarin. In addition, certain platinum-based anti-cancer agents are also effective against the disease but do produce significant side effects such as hearing loss and kidney failure. Overall, such treatments are not curative and there is an urgent need for novel therapies early in the course of the disease. We have shown that a compound which mimics an endogenous chemical in the body, adenosine, can reduce the metastasis of prostate cancer to the lung. However, we do not know how this beneficial action is produced. In addition, we would like to optimize the drug treatment to produce more reductions in lung metastasis. Therefore, these goals will form the specific aims of the current grant proposal. We believe that this study could uncover a novel method of treating prostate cancer metastasis.

描述（由申请人提供）：前列腺癌转移是前列腺癌的严重后遗症，与死亡率增加并降低治疗效率有关。雄激素戒断疗法，治疗的标志促进了肿瘤的消退。但是，平均18-24个月后的治疗益处下降，需要使用二线代理。化学治疗剂虽然有效，但无法治愈，并且迫切需要在疾病的早期开始新的疗法。我们的实验室最近表明，腺苷A3受体（A3AR）亚型的激活抑制了前列腺癌细胞的增殖和转移，而雄激素非依赖性转移性前列腺癌的大鼠和人类细胞系中的转移，并注射了AT6.1。 “转移表型”部分通过这些细胞通过NADPH氧化酶系统产生高水平的ROS来介导，NADPH氧化酶系统激活信号通路，例如核因子（NF） - ：B和细胞外信号调节激酶（ERK）有丝裂激活激活蛋白（MAP）激酶/激酶/激酶蛋白（AP-1）转录因子。通过这些机制，ROS积极调节与转移表型相关的蛋白质的表达。在此提案中，我们将检验以下假设：A3AR的激活抑制NADPH氧化酶活性，从而抑制下游信号通路，主要是ERK1/2 MAP MAP激酶和NF-：B：B和转移性基因表达，由ROS调节。在严重的合并免疫缺陷（SCID）小鼠模型中，我们将确定最佳的A3AR治疗方案，以实现转移的最大抑制作用。具体目标是：（1）确定使用A3AR激动剂减少前列腺癌转移的最佳治疗参数，重点关注最佳剂量和治疗时间表，并确定这些激动剂在建立细胞转移后是否有效。 （2）确定A3AR抑制前列腺癌细胞的ROS产生，运动和转移的机制。我们将重点关注NADPH氧化酶，并确定通过ERK1/2 MAP激酶/AP-1和NF-：B途径的激活和亚基表达的机制。总体而言，这些研究将提供有关A3AR激动剂在前列腺癌中抗转移性作用的疗效和机制的疗效和机制的新信息，并为在临床上使用该类别的药物提供了合理的基础。公共卫生相关性：前列腺癌转移是前列腺癌的严重后果，如果不治疗，可能会导致死亡。存在几种治疗选择，例如雄激素戒断疗法以及使用酮康唑和甲磷脂等药物。此外，某些基于铂的抗癌药也有效地抵抗该疾病，但确实产生了诸如听力损失和肾衰竭的重大副作用。总体而言，这种治疗方法无法治愈，并且迫切需要在疾病的早期进行新的疗法。我们已经表明，模仿体内内源性化学物质的化合物可以减少前列腺癌向肺的转移。但是，我们不知道如何产生这种有益的行动。此外，我们希望优化药物治疗，以产生更多的肺转移减少。因此，这些目标将构成当前赠款提案的具体目标。我们认为，这项研究可以揭示一种治疗前列腺癌转移的新方法。