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 comprised 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 which 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.
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