Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice.
The purpose of this study was to examine whether histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; Zolinza/vorinostat) could sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant breast carcinoma in vivo. BALB/c nude mice were orthotopically implanted with TRAIL-resistant MDA-MB-468 cells and treated i.v. with SAHA, TRAIL, or SAHA followed by TRAIL for four times during first 3 weeks. The effects of drugs on tumor growth and markers of apoptosis, metastasis, and angiogenesis were examined. SAHA sensitized TRAIL-resistant xenografts to undergo apoptosis through multiple mechanisms. Whereas TRAIL alone was ineffective, SAHA inhibited growth of MDA-MB-468 xenografts in nude mice by inhibiting markers of tumor cell proliferation, angiogenesis, and metastasis and inducing cell cycle arrest and apoptosis. The sequential treatment of nude mice with SAHA followed by TRAIL was more effective in inhibiting tumor growth, angiogenesis, and metastasis and inducing apoptosis than SAHA alone, without overt toxicity. Treatment of nude mice with SAHA resulted in down-regulation of nuclear factor-kappaB and its gene products (cyclin D1, Bcl-2, Bcl-X(L), vascular endothelial growth factor, hypoxia-inducible factor-1alpha, interleukin-6, interleukin-8, matrix metalloproteinase-2, and matrix metalloproteinase-9) and up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa, PUMA, p21(CIP1), tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in tumor cells. Furthermore, control mice showing increased rate of tumor growth had increased numbers of CD31(+) or von Willebrand factor-positive blood vessels and increased circulating vascular endothelial growth factor receptor 2-positive endothelial cells compared with SAHA-treated or SAHA plus TRAIL-treated mice. In conclusion, sequential treatment with SAHA followed by TRAIL may target multiple pathways in tumor progression, angiogenesis, and metastasis and represents a novel therapeutic approach to treat breast cancer.
Shankar
Sharmila
S
Department of Biochemistry, Center for Biomedical Research, The University of Texas Health Science Center at Tyler, 11937 U.S. Highway 271, Tyler, TX 75708-3154, USA.
Davis
Rachel
R
Singh
Karan P
KP
Kurzrock
Razelle
R
Ross
Douglas D
DD
Srivastava
Rakesh K
RK
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; D042461:Vascular Endothelial Growth Factor A; D000077337:Vorinostat; D020782:Matrix Metalloproteinases; D006655:Histone Deacetylases