Principal Investigator
Daping
Fan
Awardee Organization
University Of South Carolina At Columbia
United States
Fiscal Year
2022
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date
NIH RePORTER
For more information, see NIH RePORTER Project 3R01CA218578-05S1
Emodin as a chemopreventive agent for breast cancer
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.
- McDonald SJ, VanderVeen BN, Velazquez KT, Enos RT, Fairman CM, Cardaci TD, Fan D, Murphy EA. Therapeutic Potential of Emodin for Gastrointestinal Cancers. Integrative cancer therapies. 2022 Jan-Dec;21:15347354211067469. PMID: 34984952
- McDonald SJ, VanderVeen BN, Bullard BM, Cardaci TD, Madero SS, Chatzistamou I, Fan D, Murphy EA. Surgical wounding enhances pro-tumor macrophage responses and accelerates tumor growth and lung metastasis in a triple negative breast cancer mouse model. Physiological reports. 2022 Nov;10(21):e15497. PMID: 36325601
- Chaparala A, Tashkandi H, Chumanevich AA, Witalison EE, Windust A, Cui T, Nagarkatti M, Nagarkatti P, Hofseth LJ. Molecules from American Ginseng Suppress Colitis through Nuclear Factor Erythroid-2-Related Factor 2. Nutrients. 2020 Jun 21;12. (6). PMID: 32575883
- Chaparala A, Poudyal D, Tashkandi H, Witalison EE, Chumanevich AA, Hofseth JL, Nguyen I, Hardy O, Pittman DL, Wyatt MD, Windust A, Murphy EA, Nagarkatti M, Nagarkatti P, Hofseth LJ. Panaxynol, a bioactive component of American ginseng, targets macrophages and suppresses colitis in mice. Oncotarget. 2020 Jun 2;11(22):2026-2036. doi: 10.18632/oncotarget.27592. eCollection 2020 Jun 2. PMID: 32547701