Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)

被引:46
作者
Kubo, Makoto [1 ]
Kanaya, Noriko [1 ]
Petrossian, Karineh [1 ]
Ye, Jingjing [1 ]
Warden, Charles [2 ]
Liu, Zheng [2 ]
Nishimura, Reiki [3 ]
Osako, Tomofumi [3 ]
Okido, Masayuki [4 ]
Shimada, Kazuo [5 ]
Takahashi, Masato [6 ]
Chu, Peiguo [7 ]
Yuan, Yate-Ching [2 ]
Chen, Shiuan [1 ]
机构
[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Biol, Duarte, CA 91010 USA
[2] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA
[3] Kumamoto City Hosp, Dept Breast & Endocrine Surg, Kumamoto, Japan
[4] Hamanomachi Hosp, Dept Breast Surg, Fukuoka, Japan
[5] Shimada Breast & Surg Clin, Kitakyushu, Fukuoka, Japan
[6] Natl Hosp Org, Hokkaido Canc Ctr, Dept Breast Surg, Sapporo, Hokkaido, Japan
[7] City Hope Natl Med Ctr, Beckman Res Inst, Dept Pathol, Duarte, CA USA
关键词
Acquired aromatase inhibitor resistance; LBH589; NF-kappa B1; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; ESTROGEN-RECEPTOR; GENE-EXPRESSION; DOWN-REGULATION; LEUKEMIA-CELLS; ACETYLATION; ACTIVATION; TAMOXIFEN; INFLAMMATION;
D O I
10.1007/s10549-012-2332-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-kappa B1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-kappa B1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-kappa B1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-kappa B1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-kappa B1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-kappa B1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-kappa B1 pathway.
引用
收藏
页码:93 / 107
页数:15
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