Emodin as a chemopreventive agent for breast cancer

大黄素作为乳腺癌的化学预防剂

• 批准号: 10524241
• 负责人: Daping Fan
• 金额: $ 4.81万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524241
• 关键词: Adverse effects; Apoptosis; Aromatase Inhibitors; Blood Circulation; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Cancer Etiology; Cell Culture Techniques; Cell Proliferation; Cessation of life; Chemopreventive Agent; Chinese Herbs; Clinical Trials; Data; Development; Diagnosis; Effectiveness; Emodin; Endometrial Carcinoma; Estrogen receptor negative; Estrogen receptor positive; Event; Excision; FDA approved; Growth; Immune; Immunosuppression; Incidence; Life Style Modification; Lung; Maintenance; Malignant Neoplasms; Mediating; Metastatic breast cancer; Metastatic to; Microarray Analysis; Morbidity - disease rate; Mus; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Osteoporosis; Plants; Preventive; Primary Neoplasm; Prognosis; Publishing; Raloxifene; Rattus; Recurrence; Reporting; Risk Factors; Role; Selective Estrogen Receptor Modulators; Signal Pathway; Social Impacts; Tamoxifen; Testing; Therapeutic; Toxicology; Tumor-associated macrophages; United States; United States National Institutes of Health; Woman; angiogenesis; base; cancer cell; cancer initiation; cancer prevention; cancer stem cell; cost; economic impact; epithelial to mesenchymal transition; insight; macrophage; malignant breast neoplasm; migration; monocyte; mortality; mouse model; neoplastic cell; orthotopic breast cancer; preclinical study; prevent; prophylactic; recruit; small molecule; stemness; success; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

Summary: Breast cancer is the most prevalent cancer and the second leading cause of cancer-related death in women in the United States. However, little progress has been made in preventing the incidence of breast cancer. Most breast cancer mortality results from metastatic recurrence after initial success of surgery and/or other therapies. Although extended treatment with selective estrogen receptor modulators and aromatase inhibitors have been proven effective in preventing metastatic recurrence of breast cancer, the benefit is limited to ER+ breast cancer, and severe adverse effects make them suboptimal for long-term use. Currently there are no preventive agents for ER- breast cancer. This is of particular relevance given the high metastatic recurrence rate and the resulting poor prognosis of triple negative breast cancer. One common feature of breast cancer, regardless of the subtypes, is the pro-tumor nature of the tumor microenvironment, which contains abundant MΦs, called tumor-associated macrophages (TAMs). TAMs promote tumor development and metastasis through inducing immunosuppression, promoting angiogenesis, enhancing tumor cell proliferation and invasiveness, and facilitating cancer stem cell (CSC) formation and maintenance. Due to their determinant roles in all stages of cancer development, TAMs have been considered as a therapeutic target for cancer. However, MΦs have not yet been exploited as a target for breast cancer prevention. Emodin is a small molecule compound derived from many plants including several Chinese herbs. Our published studies showed that emodin inhibited breast cancer growth and metastasis in orthotopic mouse models through reducing MΦ recruitment to tumors and lungs and suppressing their M2-like polarization by acting on both MΦs and breast cancer cells. Our preliminary studies further showed that emodin could suppress TGFβ1-induced epithelial to mesenchymal transition and diminish the stemness of breast cancer cells, and reduce the death due to metastatic recurrence after surgical removal of primary tumors in an orthotopic breast cancer model. Importantly, a comprehensive NIH toxicology study showed that emodin is very safe for long-term use in mice and rats. Given the important roles of MΦs in breast cancer initiation and metastatic recurrence, and based on our published and preliminary data, we hypothesize that emodin can be developed as a safe and effective chemopreventive agent for breast cancer incidence and metastatic recurrence by virtue of its ability to block the tumor-promoting crosstalk between cancer cells and MΦs. Two specific aims are proposed: SA1. To determine the effects of emodin on preventing breast cancer onset and post-surgery metastatic recurrence in mouse models; and SA2. To elucidate the mechanisms by which emodin prevents breast cancer onset and metastatic recurrence. The success of the proposed preclinical studies will set a stage for clinical trials to develop emodin as a new safe, effective and low-cost chemopreventive agent for breast cancer regardless of the subtype.

摘要：乳腺癌是最常见的癌症，也是癌症相关死亡的第二大原因 然而，在美国女性中，预防乳腺疾病的进展甚微。 大多数乳腺癌死亡是由于手术初次成功后的转移性复发和/或 其他疗法虽然使用选择性雌激素受体调节剂和芳香酶进行延长治疗。 抑制剂已被证明可有效预防乳腺癌转移复发，但获益有限 ER+乳腺癌，严重的副作用使其不适合长期使用。 考虑到高转移复发率，这一点尤其重要。 三阴性乳腺癌的发病率和由此产生的不良预后是乳腺癌的一个共同特征， 无论亚型如何，肿瘤微环境都具有促肿瘤性质，其中含有丰富的 MΦ，称为肿瘤相关巨噬细胞 (TAM)，可促进肿瘤的发展和转移。 通过诱导免疫抑制、促进血管生成、增强肿瘤细胞增殖和 由于其决定因素，其具有侵袭性，并促进癌症干细胞（CSC）的形成和维持。 TAMs 在癌症发展的各个阶段都发挥着重要作用，因此被认为是癌症的治疗靶点。 然而，MΦs 尚未被开发为乳腺癌预防的靶点。 我们发表的研究表明，源自许多植物（包括几种中草药）的分子化合物。 在原位小鼠模型中，大黄素通过降低 MΦ 抑制乳腺癌生长和转移 通过作用于 MΦ 和乳腺来招募肿瘤和肺部并抑制其 M2 样极化 我们的初步研究进一步表明，大黄素可以抑制TGFβ1诱导的上皮细胞凋亡。 间质转化并减少乳腺癌细胞的干性，并减少因乳腺癌引起的死亡 原位乳腺癌模型中手术切除原发肿瘤后的转移复发。 重要的是，美国国立卫生研究院 (NIH) 的一项综合毒理学研究表明，大黄素在小鼠中长期使用非常安全 考虑到 MΦ 在乳腺癌发生和转移复发中的重要作用，并基于 根据我们已发表的初步数据，我们勇敢地相信大黄素可以被开发为一种安全有效的药物 凭借其阻断能力，成为乳腺癌发病率和转移复发的化学预防剂 提出了两个具体目标：SA1。 确定大黄素对预防乳腺癌发病和术后转移复发的作用 小鼠模型；和 SA2 阐明大黄素预防乳腺癌发生的机制。 拟议的临床前研究的成功将为临床试验奠定基础。 开发大黄素作为一种安全、有效、低成本的新型乳腺癌化学预防剂 子类型。