STAT3, G6PD and TrxR as underlying mechanisms for antitumor responses to hirsutinolides

STAT3、G6PD 和 TrxR 作为多毛内酯类抗肿瘤反应的潜在机制

• 批准号: 9443606
• 负责人: James K Turkson
• 金额: $ 50.27万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9443606
• 关键词: Amino Acids; Antitumor Response; Asia; Binding; Biology; CDC2 Protein Kinase; Cell Cycle; Cell Cycle Arrest; Cell Survival; Cells; Chemicals; Clinical Trials; Computer Simulation; DNA Binding Domain; Data; Development; Docking; Esters; Event; Gene Expression; Genes; Glioblastoma; Glioma; Glucose; Glucose-6-Phosphate; Growth; Health; Human; Hydrophobic Interactions; In Vitro; Investigation; Knowledge; Lead; Link; Metabolism; Mitosis; Mitotic; Mitotic Cell Cycle; Molecular; Mus; NADP; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Oral; Oxidation-Reduction; Oxidoreductase; PLK1 gene; Pentosephosphate Pathway; Pharmaceutical Preparations; Pharmacology; Phenotype; Plants; Positioning Attribute; Production; Property; Protein Isoforms; Publishing; Pyruvate; Reactive Oxygen Species; Recycling; Repression; Residual Tumors; Role; STAT3 gene; Series; Side; Signal Transduction; Small Interfering RNA; Smoking; Southeastern Asia; Stat3 protein; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Traditional Medicine; Tumor Cell Migration; Tumor Tissue; Up-Regulation; Vernonia; Xenograft procedure; analog; base; breast cancer progression; clinical application; clinical development; diabetes control; glucose metabolism; in vivo; insight; knock-down; malignant breast neoplasm; metabolomics; multidisciplinary; neoplastic cell; novel; oxidative damage; response; small molecule inhibitor; survivin; thioredoxin reductase; thioredoxin reductase 1; treatment strategy; triple-negative invasive breast carcinoma; validation studies

Glioblastoma multiforme (GBM) and breast cancer are major health burdens that will benefit from new mechanistic insights that lead to novel management strategies. We propose to investigate Signal Transducer and Activator of Transcription (STAT)3, thioredoxin reductase (TrxR)1 cytoplasmic isoform 3, and glucose-6-phosphate 1-dehydrogenase (G6PD) isoform a as the targeting mechanisms underlying the antitumor responses of GBM and triple-negative breast cancer to hirsutinolide compounds. The hirsutinolide series are the major chemical constituents of Vernonia cinerea. This plant has traditionally been used in Asia to treat specific ailments and in clinical trials proofed to be effective to moderate type 2 diabetes and curtail smoking. Despite the therapeutic potential of the hirsutinolides, however, little was known of their pharmacological properties to facilitate their clinical development until our studies. Our compelling data show that structurally suitable hirsutinolides strongly inhibit STAT3, TrxR1 and G6PD functions and thereby suppress breast cancer and GBM phenotypes in vitro and in vivo. Initial structure activity relationship analysis showed a critical requirement for a position 13 ester group for the activities. Unbiased computational modeling/docking and nuclear magnetic resonance structural studies show that structurally suitable hirsutinolides bind the STAT3 DNA-binding domain (DBD) via hydrophobic interactions between the position 13 side chain and specific amino acid residues in the STAT3 DBD. Select compounds caused mitotic and cell cycle arrests and inhibited growth of human breast cancer and GBM xenografts. In line with the TrxR1 or G6PD functional roles in the cellular protection against the oxidative damage from excessive reactive oxygen species (ROS) or in the pentose phosphate pathway for NADPH production, respectively, ROS levels and glycolytic metabolites, including glucose, G6P and pyruvate are significantly altered in hirsutinolide-treated tumor cells. We hypothesize that structurally suitable hirsutinolides are inherently active against STAT3, TrxR1 and G6PD functions, and alter cellular redox events and glycolytic metabolism, and thereby block breast cancer and GBM progression. We will determine the SAR of the hirsutinolides relative to inhibition of STAT3 activity and elucidate the structural determinants for STAT3 inhibition (Aim 1), investigate the mechanistic details of the STAT3 signaling inhibition by hirsutinolides and the significance to the antitumor responses against GBM and breast cancer (Aim 2), define the mechanistic link between STAT3, TrxR1 and G6PD functions, altered cellular redox recycle, metabolism, mitosis and cell cycle (Aim 3), and study the antitumor efficacy responses of select hirsutinolide analogs and their correlation to STAT3, TrxR1 and G6PD-dependent molecular and metabolomic events in vivo (Aim 4). Data will ultimately facilitate the development of the hirsutinolides as potential therapeutics for breast cancer and GBM.

多形性胶质母细胞瘤和乳腺癌是主要的健康负担，将受益于新的 机械的洞察力，导致新的管理战略。我们建议对信号进行调查 转录转导和激活因子(STAT)3、硫氧还蛋白还原酶(TrxR)1胞浆异构体3、 和葡萄糖-6-磷酸1-脱氢酶(G6PD)亚型作为潜在的靶向机制 基底膜和三阴性乳腺癌对毛状内酯类化合物的抗肿瘤作用。毛刺素内酯 系列是灰斑潜蝇的主要化学成分。这种植物传统上被用于 亚洲将治疗特定疾病，临床试验证明对中度2型糖尿病和 减少吸烟。尽管水飞蓟内酯具有治疗潜力，但人们对其知之甚少。 药理特性，以促进其临床发展，直到我们的研究。我们令人信服的数据 表明结构上合适的毛糖素内酯强烈抑制STAT3、TrxR1和G6PD功能，从而 在体外和体内抑制乳腺癌和基底膜表型。初始结构活性关系 分析表明，这些活动需要一个13位酯基团。不偏不倚 计算模拟/对接和核磁共振结构研究表明，在结构上 合适的毛囊素内酯通过STAT3DNA结合域(DBD)与STAT3DNA结合域(DBD)之间的疏水相互作用结合 STAT3DBD中第13位侧链和特定氨基酸残基。选择引起的化合物 有丝分裂和细胞周期阻断和抑制人乳腺癌和GBM异种移植瘤的生长。与…一致 TrxR1或G6PD在细胞过氧化损伤保护中的作用 用于NADPH产生的活性氧物种(ROS)或戊糖磷酸途径中， ROS水平和糖酵解代谢产物，包括葡萄糖、G6P和丙酮酸，在 水飞蓟素内酯治疗的肿瘤细胞。我们假设结构上合适的毛状内酯具有天然的活性。 抗STAT3、TrxR1和G6PD功能，改变细胞氧化还原事件和糖酵解代谢，以及 从而阻止乳腺癌和基底膜的进展。我们将测定水飞蓟内酯的相对分子质量。 为了抑制STAT3活性并阐明抑制STAT3的结构决定因素(目标1)， 探讨水飞蓟素内酯抑制STAT3信号转导的机制及其意义 针对GBM和乳腺癌的抗肿瘤反应(目标2)，确定了 STAT3、TrxR1和G6PD功能，改变细胞氧化还原循环、代谢、有丝分裂和细胞周期(AIM 3)，并研究选定的水飞蓟内酯类似物的抗肿瘤效应及其与STAT3的相关性， 体内依赖TrxR1和G6PD的分子和代谢事件(目标4)。数据最终将 促进毛状内酯作为乳腺癌和基底膜的潜在治疗药物的开发。