STAT3, G6PD and TrxR as underlying mechanisms for antitumor responses tohirsutinolides

STAT3、G6PD 和 TrxR 作为毛毛素内酯类抗肿瘤反应的潜在机制

• 批准号: 10005721
• 负责人: James K Turkson
• 金额: $ 26.28万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 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/10005721
• 关键词: STAT3; G6PD; TrxR; underlying; mechanisms

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 (GBM) 和乳腺癌是主要的健康负担，将受益于新的治疗方法 产生新颖管理策略的机制见解。我们建议调查信号 转录转导子和激活子 (STAT)3、硫氧还蛋白还原酶 (TrxR)1 细胞质亚型 3、 和葡萄糖-6-磷酸1-脱氢酶（G6PD）亚型a作为潜在的靶向机制 GBM 和三阴性乳腺癌对 hirsutinide 化合物的抗肿瘤反应。多毛素内酯 系列是斑鸠菊的主要化学成分。这种植物传统上被用于 亚洲治疗特定疾病，临床试验证明对中度 2 型糖尿病和 减少吸烟。然而，尽管多毛素内酯具有治疗潜力，但人们对它们的作用却知之甚少。 药理学特性促进其临床开发直至我们的研究。我们令人信服的数据 表明结构合适的 hirsuinolides 强烈抑制 STAT3、TrxR1 和 G6PD 功能，从而 在体外和体内抑制乳腺癌和 GBM 表型。初始结构活性关系 分析表明，13 位酯基对于该活性至关重要。不偏不倚 计算建模/对接和核磁共振结构研究表明，在结构上 合适的多毛内酯通过 STAT3 DNA 结合域 (DBD) 之间的疏水相互作用结合 STAT3 DBD 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止并抑制人类乳腺癌和 GBM 异种移植物的生长。符合 TrxR1 或 G6PD 在细胞保护中的功能作用，防止过度氧化损伤 分别在活性氧 (ROS) 或磷酸戊糖途径中产生 NADPH， ROS 水平和糖酵解代谢物（包括葡萄糖、G6P 和丙酮酸）在 多毛素内酯处理的肿瘤细胞。我们假设结构合适的多毛内酯具有固有的活性 对抗 STAT3、TrxR1 和 G6PD 功能，并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 GBM 的进展。我们将确定多毛素内酯相关物的 SAR 抑制 STAT3 活性并阐明 STAT3 抑制的结构决定因素（目标 1）， 研究 hirsuinolides 抑制 STAT3 信号传导的机制细节及其意义 针对 GBM 和乳腺癌的抗肿瘤反应（目标 2），定义两者之间的机制联系 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（目的 3)，并研究选定的多毛内酯类似物的抗肿瘤功效反应及其与 STAT3 的相关性， 体内 TrxR1 和 G6PD 依赖性分子和代谢组事件（目标 4）。数据最终将 促进 hirsuinolides 的开发作为乳腺癌和 GBM 的潜在疗法。