Journal
ONCOTARGET
Volume 8, Issue 46, Pages 80109-80123Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19019
Keywords
histone deacetylase inhibitor; breast cancer; estrogen receptor; epidermal growth factor receptor; proteasome inhibitor
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Funding
- National Institutes of Health (NIH) SPORE [CA10070, P01 78378, R01 CA50947, R01 CA178264]
- American Cancer Society
- NIH [K08CA128972]
- LeBow Family Fund
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We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ER alpha and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERa, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer.
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