Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High-Throughput Screening

PLOS ONE, Dec 2019

Overexpressed Human epidermal growth factor receptor 2 (HER2) drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

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Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High-Throughput Screening

et al. (2013) Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High- Throughput Screening. PLoS ONE 8(12): e81586. doi:10.1371/journal.pone.0081586 Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High- Throughput Screening Weihua Liu 0 Jinmei Xu 0 Shaoping Wu 0 Yilun Liu 0 Xiaoping Yu 0 Juan Chen 0 Xi Tang 0 Zhi Wang 0 Xiaohu Zhu 0 Xin Li 0 Pranela Rameshwar, Rutgers - New Jersey Medical School, United States of America 0 1 Department of Scientific Research, First Affiliated Hospital of Chengdu Medical College , Chengdu, Sichuan Province , China , 2 Department of Public Health, The Chengdu Medical College , Chengdu, Sichuan Province , China , 3 Department of Medical Image, First Affiliated Hospital of Chengdu Medical College , Chengdu, Sichuan Province , China , 4 Administrative Office of Chengdu Medical College, The Chengdu Medical College , Chengdu, Sichuan Province , China , 5 Department of Acupuncture and Moxibustion, Xindu Hospital of Traditional Chinese Medicine , Chengdu, Sichuan Province , China Overexpressed Human epidermal growth factor receptor 2 (HER2) drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3glucoside and cyaniding-3-glucoside treatments. - Funding: This work is supported by Sichuan Province Health Bureau (110465) and by the National Natural Science Foundation of China (81273074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Breast cancer is a serious and sometimes life-threatening disease. An estimated 232,340 new cases of invasive breast cancer are expected to be diagnosed among women in the US during 2013 according to American Cancer Society. Breast cancer has also become common to Chinese women in recent years possibly due to the change of environments, growth patterns, diet and aging. Based on the model generated by Linos et al., in 2021, the estimated breast cancer incidence rate would be 85.3 to 87.8 per 100,000 woman in China [1]. Evidently, there is a clear need for the development of new therapeutic agents. HER2 overexpression occurs in ,20% of patients with breast cancer and is associated with aggressive disease and decreased survival. A number of therapeutic approaches have been developed against HER2 worldwide including tyrosine kinase inhibitors, monoclonal antibodies such as Trastuzumab [2]. The mechanism has been largely studied and since then, the diseasefree survival and overall survival of patients have all been improved significantly [25]. In China, there are reports of successful novel therapeutic approaches using traditional medicine for breast cancer patients [6,7]. Traditional Chinese Herbs/ Medicines have developed into a mature system for more than three thousand years. Although thousands of Traditional Chinese Medicines have been proved to be effective clinically, the mechanisms of the drug actions are largely unclear. With the modern technology, researchers successfully purified and identified numerous extracts that have not been well defined before. With the rich prior human experiences, we proposed to screen a natural product library which contains 10,000 extracts against representative breast cancer cells and tried to identify compounds that selectively inhibit HER2-positive breast cancer cells. Materials and Methods Compound Library The natural product library contains 10,000 natural products with a minimum of 98% purity confirmed by NMR and HPLC (Pharmanic, Chengdu, Sichuan, China). Briefly, compounds were extracted by supercritical CO2 extraction (SFE-CO2) and the residues after SFE-CO2 extraction were then re (...truncated)


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Weihua Liu, Jinmei Xu, Shaoping Wu, Yilun Liu, Xiaoping Yu, Juan Chen, Xi Tang, Zhi Wang, Xiaohu Zhu, Xin Li. Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High-Throughput Screening, PLOS ONE, 2013, 12, DOI: 10.1371/journal.pone.0081586