Development of improved SRC-3 inhibitors as breast cancer therapeutic agents
| Autor: | Jin Wang, Dong Lu, Xiaobin Yu, David M. Lonard, David L. Cardenas, Xiaohui Peng, Prashi Jain, Li Qin, Yang Yu, Bert W. O'Malley, Jianwei Chen, Jianming Xu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Epithelial-Mesenchymal Transition Endocrinology Diabetes and Metabolism Breast Neoplasms Article Metastasis Nuclear Receptor Coactivator 3 Mice Endocrinology Breast cancer Cell Movement Cell Line Tumor medicine Animals Humans Receptor Transcription factor Cell Proliferation business.industry Cancer Oncogenes medicine.disease Xenograft Model Antitumor Assays Oncology Nuclear receptor Tumor progression Cancer research Female business Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Endocr Relat Cancer |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-20-0402 |
| Popis: | Steroid receptor coactivators (SRCs) possess specific and distinct oncogenic roles in the initiation of cancer and in its progression to a more aggressive disease. These coactivators interact with nuclear receptors and other transcription factors to boost transcription of multiple genes, which potentiate cancer cell proliferation, migration, invasion, tumor angiogenesis and epithelial–mesenchymal transition (EMT). Targeting SRCs using small molecule inhibitors (SMIs) is a promising approach to control cancer progression and metastasis. By high-throughput screening analysis, we recently identified SI-2 as a potent SRC SMI. To develop therapeutic agents, SI-10 and SI-12, the SI-2 analogs are synthesized that incorporate the addition of F atoms to the SI-2 chemical structure. As a result, these analogs exhibit a significantly prolonged plasma half-life, minimal toxicity and improved hERG activity. Biological functional analysis showed that SI-10 and SI-12 treatment (5–50 nM) can significantly inhibit viability, migration and invasion of breast cancer cells in vitro and repress the growth of breast cancer PDX organoids. Treatment of mice with 10 mg/kg/day of either SI-10 or SI-12 was sufficient to repress the growth of xenograft tumors derived from MDA-MB-231 and LM2 cells. Furthermore, in spontaneous and experimental metastasis mouse models developed from MDA-MB-231 and LM2 cells, respectively, SI-10 and SI-12 effectively inhibited the progression of breast cancer lung metastasis. These results demonstrate that SI-10 and SI-12 are promising therapeutic agents and are specifically effective in blocking tumor metastasis, a key point in tumor progression to a more lethal state that results in patient mortality in the majority of cases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|