Chemoprevention Efficacy of Sulforaphane Against Obesity-Induced Endometrial Carcinogenesis

肥胖的流行导致了子宫内膜癌(EC)发病率和死亡率的增加。 在美国，特别是在年轻女性中。尽管食道癌与良好的预后有关， 与其他癌症相比，由于荷尔蒙的丢失，手术仍然是食道癌患者治疗的基石。 在超过30%的病例中，受体导致了荷尔蒙抵抗。然而，手术并不是一个好的选择。 肥胖相关的合并症，以及育龄妇女，这阻碍了个人参加竞选 外科手术。因此，需要更新的预防策略来减少EC的发病率、发病率、 死亡率，并挽救生育能力。在寻找新的EC预防药物方面，我们在体内和体外证明了萝卜硫素(SFN)的显著抗癌活性，SFN是一种天然存在的饮食异硫氰酸酯。 此外，它还具有抑制EC中组蛋白脱乙酰酶(HDAC)的活性。由于在正常情况下没有明显的毒性 细胞，SFN作为一种人类癌症防御剂已经引起了极大的关注：目前，有几个正在进行的 I期和II期临床试验正在评估其在不同类型癌症中的化学预防作用。 此外，最近的研究已经确定了SFN在肥胖和肥胖相关疾病的管理中的关键作用。SFN已被证明调节脂肪生成和脂肪生成，以及细胞凋亡和 脂肪细胞中的脂解作用。由于对关键危险因素肥胖的调节，以及EC的消退或治疗 前驱病变，如子宫内膜增生症(AEH/EH)到正常子宫内膜是合理的方法 为了防止EC的发展，我们假设SFN是一种很有前途的EC化学预防药物，因为它 调节肥胖和对子宫内膜施加抗增殖活性的能力。我们还预计人类发展援助委员会 抑制SFN的活性将有助于提高孕酮治疗的敏感性 黄体酮受体。因此，在本研究中，我们建议建立一种肥胖相关的动物模型。 目的：探讨肥胖与AEH/EH发病的内在机制及相互关系。我们 此外，还计划评估SFN单独或与黄体酮联合应用的化学预防效果 探讨三七总皂苷在肥胖相关EH/AEH动物模型中的减肥作用机制。这个项目很适合 在父母赠款目标范围内，提高护理标准，改善所有符合以下条件的妇女的临床结果 妇科癌症，重点解决与俄克拉荷马州相关的癌症问题。俄克拉荷马州已经 肥胖率最高，营养和妇女保健方面的记录最差。这个 从这项研究中获得的肥胖如何驱动EC的机械洞察力将被用于开发新的分子 有针对性的干预策略。建立SFN作为治疗AEH的替代方案可能会提供更少的 针对EC的侵入性且成本较低的预防策略。此外，将SFN用作儿童的膳食补充剂 消除AEH/EH或防止其发展为癌症将提供一个独特的机会，以避免 生育能力丧失以及手术和化疗的并发症。

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.