Chemoprevention Efficacy of Sulforaphane Against Obesity-Induced Endometrial Carcinogenesis

萝卜硫素对肥胖引起的子宫内膜癌的化学预防作用

• 批准号: 10285647
• 负责人: ROBERT S. MANNEL
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285647
• 关键词: Address; Adipocytes; Adipose tissue; Animal Model; Anti-Obesity Agents; Apoptosis; Attention; Attenuated; Atypical Endometrial Hyperplasias; Atypical hyperplasia; Biological Markers; Body fat; CCAAT-Enhancer-Binding Protein-alpha; Cancer Patient; Chemoprevention; Chemopreventive Agent; Cholesterol; Clinical; Clinical Management; Clinical Trials; Combined Modality Therapy; Complex; Deposition; Development; Dietary Isothiocyanate; Disease; Disease Outcome; Down-Regulation; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrium; Estrogens; Fatty acid glycerol esters; Female; Female of child bearing age; Fertility; Future; Geographic state; Glucose; Goals; Healthcare; High Density Lipoprotein Cholesterol; Histone Deacetylase; Histone Deacetylase Inhibitor; Hormonal; Hormone Receptor; Human; Hysterectomy; In Vitro; Incidence; Individual; Infertility; Insulin; Intervention; LDL Cholesterol Lipoproteins; Leptin; Lesion; Lipolysis; Liver; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Measurement; Mediating; Metabolism; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Normal Cell; Obesity; Obesity Epidemic; Oklahoma; Operative Surgical Procedures; Outcome; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Prevalence; Prevention; Prevention strategy; Prevention trial; Preventive; Progesterone; Progesterone Receptors; Progestins; Prognosis; Receptor Signaling; Records; Regulation; Resistance; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Sulforaphane; Surgical complication; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; TimeLine; Tissues; Toxic effect; Triglycerides; United States; Up-Regulation; Uterus; Woman; Women' s Health; adiponectin; base; cancer cell; cancer surgery; cancer therapy; cancer type; carcinogenesis; chemotherapy; comorbidity; cost; diet-induced obesity; dietary supplements; early-onset obesity; endometrial cancer prevention; fertility preservation; hormone therapy; improved; in vivo; inflammatory marker; insight; lipid biosynthesis; mortality; novel; novel therapeutic intervention; nutrition; obesity development; obesity management; obesity treatment; operation; parent grant; preclinical efficacy; preclinical study; premalignant; prevent; standard of care; translational study; treatment trial; tumor progression; young woman

The obesity epidemic has contributed to increased incidence and mortality of endometrial cancer (EC) in the United States, particularly among younger women. Although EC is associated with a good prognosis in comparison to other cancers, surgery remains the cornerstone therapy for EC patients due to loss of hormone receptors contributing hormonal resistance in more than 30% cases. However, surgery is not a good option for obesity-related co-morbid conditions, and women of childbearing age, which prevents individual’s candidacy for surgical operation. Therefore, newer prevention strategies are needed to reduce EC incidence, morbidity, mortality, and to save fertility. In the search for new preventive drugs for EC, we demonstrated significant anticancerous activity of sulforaphane (SFN), a naturally occurring dietary isothiocyanate, in-vivo and in-vitro, in addition to its Histone deacetylase (HDAC) inhibition activity in EC. Due to the lack of significant toxicity in normal cells, SFN has garnered significant attention as a cancer preventive agent for humans: currently, several ongoing phase-I and phase-II clinical trials are evaluating its chemo-preventive role in different types of cancers. Furthermore, recent studies have established SFN’s critical role in the management of obesity and obesityrelated disorders. SFN has been shown to regulate adipogenesis and lipogenesis, as well as apoptosis and lipolysis in adipocytes. Since regulation of the key risk factor, obesity, as well as regression or treatment of EC precursor lesions such as endometrial hyperplasia (AEH/EH) to normal endometrium are rational approaches to prevent EC development, we hypothesized that SFN is a promising chemo-preventive agent for EC due to its ability to regulate obesity and exert anti-proliferative activity on the endometrium. We also expect that the HDAC inhibition activity of SFN will contribute to enhanced sensitivity of progesterone therapy via upregulation of the progesterone receptors. Therefore, in this study, we propose to develop an obesity-associated animal model of AEH/EH to explore the underlying mechanism and association of obesity with the development of AEH/EH. We also plan to evaluate the chemo-preventive efficacy of SFN alone or in combination with progesterone besides exploring the anti-obesity mechanism of SFN in our obesity associated EH/AEH animal model. This project fits within the parent grant goal to raise the standard of care and improve clinical outcomes for all women with gynecologic cancers with an emphasis on addressing cancer problems relevant to Oklahoma. Oklahoma has highest rates of obesity and worst records of the US States for nutrition and women’s health care. The mechanistic insight into how obesity drives EC, gained from this study will be used to develop novel molecularly targeted intervention strategies. Establishing SFN as a therapeutic alternative for AEH may provide a less invasive and less costly preventive strategy for EC. Furthermore, the use of SFN as a dietary supplement for the elimination of AEH/EH or prevention of its progression to cancer would provide a unique opportunity to avoid the loss of fertility and complications of surgery and chemotherapy.

肥胖流行有助于增加子宫内膜癌的发病率和死亡率（EC） 美国，特别是在年轻妇女中。尽管EC与一个很好的提示有关 与其他癌症进行比较，由于雌马的损失，手术仍然是EC患者的基石疗法 在30％以上的病例中，受到激素抗性的受体。但是，手术不是一个不错的选择 与肥胖相关的合并状况和生育年龄的妇女，这阻止了个人的候选人 手术。因此，需要新的预防策略来减少EC事件，发病率， 死亡率，并节省生育能力。在寻找EC的新预防药物时，我们显示了一种天然存在的异硫氰酸盐硫烷（SFN）的显着抗抗气活性 在EC中增加了其组蛋白脱乙酰基酶（HDAC）抑制活性。由于正常缺乏明显的毒性 细胞，SFN作为人类的癌症预防剂引起了极大的关注：目前，有几个正在进行 I期和II期临床试验正在评估其在不同类型的癌症中的化学预防作用。 此外，最近的研究确立了SFN在肥胖和肥胖相关疾病的管理中的关键作用。已显示SFN调节脂肪生成和脂肪生成，凋亡和凋亡和 脂肪细胞中的脂解。自关键危险因素，肥胖以及EC的回归或治疗 前体病变（例如子宫内膜增生（AEH/EH））正常子宫内膜是合理的方法 防止EC的发展，我们假设SFN是EC的承诺化学预防剂 调节肥胖症并在子宫内膜上发挥抗增殖活性的能力。我们还期望HDAC SFN的抑制活性将有助于通过上调 孕酮受体。因此，在这项研究中，我们建议开发与目标相关的动物模型 aeh/eh探索肥胖与AEH/EH的发展的潜在机制和关联。我们 还计划单独评估SFN的化学预防效率或与孕酮结合 探索SFN与肥胖相关的EH/AEH动物模型中SFN的抗肥胖机制。这个项目适合 在父母赠款的目标中，提高护理标准并改善了所有患有所有女性的临床结果 妇科癌症强调解决与俄克拉荷马州有关的癌症问题。俄克拉荷马州有 美国营养和妇女医疗保健的肥胖和最差记录。这 从这项研究中获得的肥胖驱动EC的机理洞察力将用于开发新的分子 有针对性的干预策略。建立SFN作为AEH的治疗替代品可能会更少 EC的侵入性和成本较低的预防策略。此外，将SFN用作饮食补充剂 消除AEH/EH或预防其发展为癌症将提供独特的机会，以避免 生育能力和手术和化学疗法的并发症的丧失。