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.