MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo.

Abstract

Histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) show promise for the treatment of cancers. The purpose of this study was to examine the molecular mechanisms by which HDAC inhibitor MS-275 sensitizes TRAIL-resistant breast cancer cells in vivo, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition (EMT). BALB/c nude mice were orthotopically implanted with TRAIL-resistant invasive breast cancer MDA-MB-468 cells and treated intravenously with MS-275, TRAIL, or MS-275 followed by TRAIL, 4 times during first 3 weeks. Treatment of mice with TRAIL alone had no effect on tumor growth, metastasis, angiogenesis, and EMT. In comparison, MS-275 sensitized TRAIL-resistant xenografts by inducing apoptosis, inhibiting tumor cell proliferation, angiogenesis, metastasis, and reversing EMT. Treatment of nude mice with MS-275 resulted in downregulation of NF-κB and its gene products (cyclin D1, Bcl-2, Bcl-X(L), VEGF, HIF-1α, IL-6, IL-8, MMP-2, and MMP-9) and upregulation of DR4, DR5, Bax, Bak, and p21(/CIP1) in tumor cells. Furthermore, MS-275-treated mice showed significantly reduced tumor growth and decreased circulating vascular VEGFR2-positive endothelial cells, CD31-positive or von Willebrand factor-positive blood vessels, and lung metastasis compared with control mice. Interestingly, MS-275 caused "cadherin switch" and reversed EMT as shown by the upregulation of E-cadherin and downregulation of N-cadherin and transcription factors Snail, Slug, and ZEB1. In conclusion, sequential treatments of mice with MS-275 followed by TRAIL may target multiple pathways to reverse EMT and inhibit tumor progression, angiogenesis, and metastasis and represent a novel therapeutic approach to treat cancer.

• Authors: Rakesh K Srivastava, Razelle Kurzrock, Sharmila Shankar
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 12 Pg. 3254-66 (Dec 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 21041383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Neoplasm Proteins
• Pyridines
• TNF-Related Apoptosis-Inducing Ligand
• entinostat
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Benzamides (pharmacology, therapeutic use)
• Breast Neoplasms (blood supply, drug therapy, enzymology, pathology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Proteins (metabolism)
• Neovascularization, Pathologic (drug therapy)
• Pyridines (pharmacology, therapeutic use)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Xenograft Model Antitumor Assays