Chemopreventive Activity of Selenium-Derivatives of Celecoxib in Melanoma

描述(由申请人提供)： 本申请是为了响应PA的一项名为“癌症预防研究小额资助计划(PAR-06-313)”的申请。我们提出的研究的主要目的是研究一种新的组合--硒(Se)和塞来昔布(一种选择性环氧合酶-2(COX-2)抑制剂)在早期黑色素瘤发生中的有益化学预防作用。恶性黑色素瘤是最致命的皮肤癌。虽然黑色素瘤约占所有皮肤癌的4%，但它是皮肤癌死亡的77%以上的原因。因此，新的治疗策略对于黑色素瘤的治疗是必要的，因为传统的治疗方法是无效的。促血管生成的前列腺素E2(PGE2)在黑色素瘤中的作用主要归因于COX-2表达的加剧。根据我们之前的研究，抗氧化剂Se通过使氧化还原敏感的转录因子NF-βB失活，导致广泛的哺乳动物细胞中COX-2的表达显著下调。这可能是黑色素瘤患者的一个关键问题，因为他们的血浆Se水平显著降低。将塞来昔布和硒整合为一种新的治疗化合物的组合方法将在重建的皮肤模型和免疫缺陷小鼠中测试其对人恶性黑色素瘤细胞系增殖和早期黑色素瘤发展的影响。本文提出的研究是基于这样一种假设：在实验性早期黑色素瘤模型中，补充Se的同时抑制COX-2的表达和活性有助于延缓癌变的发生。这一假设将在以下特定目标进行验证：1)基于对人COX-2活性部位的定量结构功能分析合成塞来昔布的硒衍生物；2)检测塞来昔布衍生物对人黑色素瘤细胞系COX-2表达/活性和核因子-βB激活的有效性；以及3)在体外重建的皮肤模型中检测塞来昔布对黑色素瘤发生的化学预防作用及其产生小鼠皮下肿瘤的能力。总而言之，从这个项目收集的初步数据将证明中心假设是正确的，并值得进一步深入研究。这里提出的研究将需要充分支持大规模赠款申请的具体目标。

DESCRIPTION (provided by applicant): This application is submitted in response to a PA entitled "Cancer prevention research small grant program (PAR-06-313)". The primary objective of our proposed studies is to investigate the beneficial chemopreventive effects of a novel combination of selenium (Se), an essential micronutrient, and celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in the development of early melanoma. Malignant melanoma is the most deadly form of skin cancer. While melanoma accounts for roughly 4% of all skin cancers, it is responsible for more than 77% of skin cancer deaths. Thus, novel therapeutic strategies are warranted for the treatment of melanoma as conventional therapies are inefficient. The role of pro-angiogenic prostaglandin E2 (PGE2), which is increased in melanoma, can be mainly attributed to exacerbated expression of COX-2. Based on our previous research, antioxidant Se causes a significant down-regulation of COX-2 expression in a wide range of mammalian cells via the inactivation of the redox-sensitive transcription factor, NF-?B. This could be a key issue in melanoma patients as their plasma levels of Se are significantly reduced. A combinatorial approach that integrates celecoxib and Se into one novel therapeutic compound will be tested for its effect on the proliferation and early development of melanoma by human malignant melanoma cells lines in reconstructed skin models and immunodeficient mice. Studies proposed here are based on the hypothesis that Se supplementation coupled to inhibition of COX-2 expression and activity aids in the retardation of cancerous lesions in experimental models of early melanoma. The hypothesis will be tested in the following Specific Aims: 1) Synthesis of Se-derivatives of celecoxib based on quantitative structure-function analysis of human COX-2 active site; 2) To examine the efficacy of Se-celecoxib derivatives on COX-2 expression/activity and NF-?B activation in human melanoma cell lines, and 3) To examine the chemopreventive effects of Se- celecoxibs on the development of melanoma in the in-vitro reconstructed skin models and their ability to generate subcutaneous tumors in mice. Collectively, preliminary data collected from this program will establish that the central hypothesis is correct and warrants further in-depth research. Studies proposed here will be needed to adequately support the specific aims of a large grant application.