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

基本信息

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
项目类别：
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

项目摘要

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）：癌细胞中信号传感器和转录3（STAT3）蛋白激活因素的组成型激活被认为可以促进细胞增殖和血管生成，抑制凋亡，并驱动对入侵和转移重要的基因。因此，抑制STAT3代表了大部分恶性肿瘤的癌症治疗方法。 STAT3抑制的一种有希望的铅化合物是天然产物姜黄素。姜黄素在许多模型中具有抗癌特性，已被证明可以抑制包括STAT3在内的各种细胞靶标。姜黄素的分子结构表明该分子以两种不同的互变异组形式存在：1）二酮形式（-keto）和2）酮 - 烯醇（-enol）形式。我们小组进行的计算化学和结构性关系的初步研究预测，姜黄素的二旋转激体剂但不能抑制STAT3二聚化。因此，我们设计了锁定在二甲苯中的新型姜黄素类似物，目的是提高STAT3作为分子靶标的特异性。该提案中包含的初步数据表明，早期类似物对STAT3高度特异，并在体外诱导有效的促凋亡作用。我们假设可以操纵姜黄素的双肌互变异素形式，从而通过抑制STAT3磷酸化和二聚化来对黑色素瘤细胞产生增强的促凋亡活性。为了检验这一假设，我们建议开发可溶性，代谢稳定的小分子姜黄素类似物，这些类似物专门抑制STAT3 SH2 SH2磷酸化和二聚化（AIM 1）。随后将在体外评估所得的STAT3抑制性姜黄素类似物的促凋亡作用（AIM 2）。对于这些研究，黑色素瘤细胞将被用作模型，因为它代表了一种高度化学抗性的肿瘤，其中STAT3被认为起主要作用。最后，我们将确定使用姜黄素或其所得类似物的STAT3抑制是否可以增加I型I型和II型干扰素在黑色素瘤细胞上的直接抗肿瘤作用（AIM 3）。从这些研究中得出的数据将通过研究一种源自天然化合物的新颖的靶向剂来支持互补方法的癌症护理方法。 AIM 3中提出的研究将扩展我们对测试姜黄素的靶向抑制剂的重点，也可以用于增强细胞因子传统黑色素瘤治疗的抗肿瘤作用（例如，干扰素）。最终，从这些研究中获得的知识将指导未来的转化研究，以设计黑色素瘤的新型治疗策略以及STAT3发挥作用的任何其他癌症。公共卫生相关性：姜黄素是源自饮食中的香料“姜黄”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，可以对姜黄素的化学结构进行修饰，以使其更特异性对于一种在癌细胞中高活性的蛋白质。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。我们还将确定这种修饰的姜黄素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。