Evaluating the anti-tumor effects of novel curcumin analogs in melanoma

评估新型姜黄素类似物对黑色素瘤的抗肿瘤作用

• 批准号: 7897164
• 负责人: Gregory B. Lesinski
• 金额: $ 19.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897164
• 关键词: Apoptosis; Apoptotic; Biochemistry; Biological Assay; Biological Availability; Biological Factors; Breast; Cancer Biology; Cancer Model; Cell Proliferation; Cells; Chemical Structure; Clinical Data; Curcuma; Curcumin; Cutaneous Melanoma; Data; Development; Dimerization; Disease; Dose-Limiting; Drug resistance; Figs - dietary; Future; Generations; Genes; Goals; Human; In Vitro; Incidence; Interferon Type II; Interferons; Knowledge; Lead; Lung; Malignant Neoplasms; Melanoma Cell; Metabolic; Modeling; Molecular; Molecular Structure; Molecular Target; Names; Neoplasm Metastasis; Oncogenic; Pancreas; Patients; Pharmaceutical Chemistry; Pharmacology; Phenotype; Phosphorylation; Play; Property; Proteins; Reagent; Relative (related person); Research; Resistance; Rhizome; Role; STAT protein; Signal Transduction; Site; Skin Cancer; Solubility; Specificity; Spices; Stat3 protein; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Translational Research; Tumeric; analog; angiogenesis; base; cancer care; cancer cell; cancer therapy; cancer type; cellular targeting; computational chemistry; cytokine; cytotoxicity; density; design; diketone; drug standard; effective therapy; enol; functional group; improved; inhibitor/antagonist; innovation; killings; melanoma; multidisciplinary; novel; novel strategies; novel therapeutics; outcome forecast; public health relevance; research study; response; scaffold; small molecule; src Homology Region 2 Domain; tautomer; tumor

DESCRIPTION (provided by applicant): Constitutive activation of the signal transducer and activator of transcription-3 (STAT3) protein in cancer cells is thought to promote cell proliferation and angiogenesis, inhibit apoptosis, and drive genes important for invasion and metastasis. Therefore inhibition of STAT3 represents a rational approach to cancer therapy for a large proportion of malignancies. One promising lead compound for STAT3 inhibition is the natural product, curcumin. Curcumin has anti-cancer properties in numerous models and has been shown to inhibit a variety of cellular targets including STAT3. The molecular structure of curcumin indicates that the molecule exists in two distinct tautomeric forms: 1) a diketone form (-keto) and 2) an keto-enol (-enol) form. Computational chemistry and structure-activity-relationship preliminary studies conducted by our group have predicted that the diketo- tautomer but not the enol-tautomer of curcumin can inhibit STAT3 dimerization. Therefore, we have designed novel curcumin analogs locked into the diketo form with the goal of enhancing the specificity for STAT3 as a molecular target. Preliminary data contained within this proposal demonstrate that early generation analogs are highly specific for STAT3, and induce potent pro-apoptotic effects in vitro. We hypothesize that the diketo- tautomer form of curcumin can be manipulated to produce enhanced pro-apoptotic activity on melanoma cells by inhibiting STAT3 phosphorylation and dimerization. To test this hypothesis, we propose to develop soluble, metabolically stable, small molecule curcumin analogs that specifically inhibit STAT3 SH2 phosphorylation and dimerization (Aim 1). The pro-apoptotic effects of the resulting STAT3-inhibitory curcumin analogs will subsequently be evaluated in vitro (Aim 2). For these studies, melanoma cells will be used as a model as it represents a highly chemo-resistant tumor in which STAT3 is thought to play a major role. Finally, we will determine if STAT3 inhibition with curcumin or its resulting analogs can serve to augment the direct anti-tumor actions of Type I and Type II interferons on melanoma cells (Aim 3). The data derived from these studies will support the development of complementary approaches to cancer care by investigating a novel, targeted agent derived from a natural compound. The studies proposed in Aim 3 will extend our focus on testing whether STAT3-targeted inhibitors derived from curcumin could also be used to augment the anti-tumor effects of conventional melanoma therapy with cytokines (e.g. the interferons). Ultimately, knowledge gained from these studies will guide future translational research to devise novel therapeutic strategies for melanoma and any other cancer in which STAT3 plays a role. PUBLIC HEALTH RELEVANCE: Curcumin is a natural product derived from the dietary spice 'turmeric' that has been shown to kill cancer cells in culture. Preliminary experiments performed by our research group have shown that the chemical structure of curcumin can be modified to make it more specific for a protein named STAT3 that is highly active in cancer cells. We propose to further modify this chemical structure to more effectively kill melanoma skin cancer cells. We will also determine if this modified derivative of curcumin can enhance the ability of standard drugs (called interferons) to kill cancer cells.

描述（由申请人提供）：癌细胞中信号转导子和转录激活子 3 (STAT3) 蛋白的组成性激活被认为可促进细胞增殖和血管生成、抑制细胞凋亡并驱动对侵袭和转移重要的基因。因此，抑制 STAT3 代表了大部分恶性肿瘤的合理癌症治疗方法。一种有前景的抑制 STAT3 的先导化合物是天然产物姜黄素。姜黄素在多种模型中具有抗癌特性，并已被证明可以抑制多种细胞靶标，包括 STAT3。姜黄素的分子结构表明该分子以两种不同的互变异构形式存在：1) 二酮形式 (-keto) 和 2) 酮-烯醇 (-enol) 形式。本课题组通过计算化学和构效关系初步研究预测，姜黄素的二酮互变异构体能够抑制STAT3二聚化，而烯醇互变异构体则不能。因此，我们设计了锁定二酮形式的新型姜黄素类似物，目的是增强 STAT3 作为分子靶点的特异性。该提案中包含的初步数据表明，早期一代类似物对 STAT3 具有高度特异性，并在体外诱导有效的促凋亡作用。我们假设姜黄素的二酮互变异构体形式可以通过抑制 STAT3 磷酸化和二聚化来增强黑色素瘤细胞的促凋亡活性。为了检验这一假设，我们建议开发可溶的、代谢稳定的小分子姜黄素类似物，专门抑制 STAT3 SH2 磷酸化和二聚化（目标 1）。随后将在体外评估所得 STAT3 抑制姜黄素类似物的促凋亡作用（目标 2）。在这些研究中，黑色素瘤细胞将被用作模型，因为它代表了一种高度化疗耐药的肿瘤，STAT3被认为在其中发挥着主要作用。最后，我们将确定姜黄素或其产生的类似物抑制 STAT3 是否可以增强 I 型和 II 型干扰素对黑色素瘤细胞的直接抗肿瘤作用（目标 3）。这些研究获得的数据将通过研究一种源自天然化合物的新型靶向药物，支持癌症护理补充方法的开发。目标 3 中提出的研究将扩展我们对测试源自姜黄素的 STAT3 靶向抑制剂是否也可用于增强细胞因子（例如干扰素）传统黑色素瘤治疗的抗肿瘤作用的关注。最终，从这些研究中获得的知识将指导未来的转化研究，为黑色素瘤和 STAT3 发挥作用的任何其他癌症设计新的治疗策略。 公共健康相关性：姜黄素是一种从膳食香料“姜黄”中提取的天然产品，已被证明可以杀死培养物中的癌细胞。我们的研究小组进行的初步实验表明，可以修改姜黄素的化学结构，使其对癌细胞中高度活跃的名为 STAT3 的蛋白质更具特异性。我们建议进一步修改这种化学结构，以更有效地杀死黑色素瘤皮肤癌细胞。我们还将确定姜黄素的这种修饰衍生物是否可以增强标准药物（称为干扰素）杀死癌细胞的能力。