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Cited by 168Phytochemistry and Bioactive CompoundsNatural Compounds in Disease TreatmentNatural product bioactivities and synthesis

Bufalin Is a Potent Small-Molecule Inhibitor of the Steroid Receptor Coactivators SRC-3 and SRC-1

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Wang, Ying, Lonard, David M., Yu, Yang, Chow, Dar-Chone, Palzkill, Timothy G., Wang, Jin, Qi, Ruogu, Matzuk, Alexander J. +9 more·2014·Cancer Research
DOI 10.1158/0008-5472.can-13-2939PMC PMC3947477
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Abstract

Virtually all transcription factors partner with coactivators that recruit chromatin remodeling factors and interact with the basal transcription machinery. Coactivators have been implicated in cancer cell proliferation, invasion, and metastasis, including the p160 steroid receptor coactivator (SRC) family composed of SRC-1 (NCOA1), SRC-2 (TIF2/GRIP1/NCOA2), and SRC-3 (AIB1/ACTR/NCOA3). Given their broad involvement in many cancers, they represent candidate molecular targets for new chemotherapeutics. Here, we report on the results of a high-throughput screening effort that identified the cardiac glycoside bufalin as a potent small-molecule inhibitor for SRC-3 and SRC-1. Bufalin strongly promoted SRC-3 protein degradation and was able to block cancer cell growth at nanomolar concentrations. When incorporated into a nanoparticle delivery system, bufalin was able to reduce tumor growth in a mouse xenograft model of breast cancer. Our work identifies bufalin as a potentially broad-spectrum small-molecule inhibitor for cancer. Cancer Res; 74(5); 1506–17. ©2014 AACR.

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  • Bufalin could suppress multiple signaling pathways, including Hippo-YAP, Wnt/β-Catenin, JNK, SRC3/MIF, mTOR, and MAPK, leading to apoptosis, necrosis, and autophagy in different cancer cells.

    “Current pharmacological research suggests that Bufalin could suppress multiple signaling pathways, including Hippo-YAP, Wnt/β-Catenin, JNK, SRC3/MIF, mTOR, and MAPK, leading to apoptosis, necrosis, and autophagy in different cancer cells3,5–8.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [8]

    The Results sections on SRC-3 degradation and cancer-cell proliferation report that bufalin reduces SRC-3 protein levels and inhibits growth of the cancer cells tested. The section on targeted therapeutics links SRC-3 to PI3K/AKT/mTOR signaling, but does not establish that bufalin suppresses mTOR. These passages do not support the other named pathways, the SRC3/MIF pairing, or the specified outcomes of apoptosis, necrosis, and autophagy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Bufalin has been shown to downregulate expression of transcriptional coactivators SRC-1 and SRC-3, as well as nuclear transcription factor E2F1.

    “Furthermore, Bufalin has been shown to downregulate the expression of transcriptional coactivators SRC-1 and SRC-3, as well as the nuclear transcription factor E2F18,43.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [8]

    The Results section ('Effects of digoxin and bufalin on cellular protein concentrations') reports that bufalin significantly reduced SRC-1 and SRC-3 protein levels in MCF-7 and A549 cells. The Introduction mentions E2F1 only as a transcription factor coactivated by SRC proteins; our copy does not report that bufalin downregulates E2F1. Page numbers were not available in the indexed passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Previous studies have reported that Bufalin exerts anti-tumor effects by inhibiting SRC in MCF-7 cells.

    “Previous studies have reported that Bufalin exerts anti-tumor effects by inhibiting SRC in MCF-7 cells8.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [8]

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Research works printed but not linked: 47

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Authors
Wang, Y., Lonard, D. M., Yu, Y., Chow, D.-C., Palzkill, T. G., Wang, J., Qi, R., Matzuk, A. J., Song, X., Madoux, F., Hodder, P., Chase, P., Griffin, P. R., Zhou, S., Liao, L., Xu, J., & O'Malley, B. W.
Affiliations
  • Scripps Research Institute (US)
  • Authors' Affiliations: Departments of 1Molecular and Cellular Biology and 2Pharmacology, Baylor College of Medicine, Houston, Texas; and 3Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida
Corresponding author
Lonard, David M.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-03-01
Volume
74
Issue
5
Pages
1506-1517
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-13-2939
PMC
PMC3947477
OpenAlex
W2129833757
Cited by
168
References
52
Citations by year
2026: 5 · 2025: 12 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 14 · 2020: 19 · 2019: 13 · 2018: 12 · 2017: 17 · 2016: 20 · 2015: 18 · 2014: 8
FWCI
7.94
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (U54MH084512)
  • National Cancer Institute (R01CA112403)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK059820, P01DK059820)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD076596, U01HD076596, R01HD008188, R01HD007857)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Phytochemistry and Bioactive Compounds
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
Keywords
bufalin, steroid receptor coactivators, SRC-3, SRC-1, NCOA3, cardiac glycosides, small molecule inhibitors, protein degradation, breast cancer, nanoparticle drug delivery, tumor growth inhibition, high-throughput screening
MeSH terms
Animals, Bufanolides, Cell Line, Digoxin, HeLa Cells, Humans, Transcription Factors, Mice, SCID, Cell Line, Tumor, Cell Proliferation, Mice, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivator 3, MCF-7 Cells

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