MS-275 sensitizes TRAIL-resistant breast cancer cells, inhibits angiogenesis and metastasis, and reverses epithelial-mesenchymal transition in vivo.
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.
Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Rakesh K
RK
Srivastava
Razelle
R
Kurzrock
Sharmila
S
Shankar
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D011725:Pyridines; D053221:TNF-Related Apoptosis-Inducing Ligand; C118739:entinostat; D053148:Caspase 3