The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.
The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.
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DOI：
10.1186/1471-2407-13-286
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发表时间：
2013-06-13
期刊：
影响因子：
3.8
通讯作者：
Frühwald M
中科院分区：
文献类型：
--
作者：
Kerl K;Ries D;Unland R;Borchert C;Moreno N;Hasselblatt M;Jürgens H;Kool M;Görlich D;Eveslage M;Jung M;Meisterernst M;Frühwald M
横纹肌样瘤是一种高度侵袭性的恶性肿瘤，影响婴儿和幼儿。在许多情况下，这些肿瘤对常规类型的化疗有抗性，需要替代方法。采用MTT法、细胞凋亡（碘化丙啶/膜联蛋白V）、细胞周期分析（DAPI）、RNA表达微阵列和蛋白质印迹法，研究组蛋白去乙酰化酶（HDAC）抑制剂SAHA与芬维A胺、他莫昔芬和阿霉素对横纹肌样瘤细胞系的协同作用。HDAC 1和HDAC 2在原发性横纹肌样肿瘤和横纹肌样肿瘤细胞系中过表达。靶向横纹肌样肿瘤中的HDAC诱导细胞周期停滞和细胞凋亡。另一方面，HDAC抑制诱导横纹肌样肿瘤中基因程序（MYCC-、RB程序和干细胞程序）失调。这些程序通常与细胞周期进展相关。通过HDAC抑制剂加芬维A胺（其抑制细胞周期蛋白D1）的组合方法靶向这些活化的促增殖基因，对诱导细胞凋亡表现出强的协同作用。此外，HDAC抑制使横纹肌样肿瘤细胞系对化疗诱导的细胞死亡敏感。我们的数据表明，HDAC抑制剂治疗与芬维A胺或常规化疗的组合是一种有前途的工具，用于治疗化疗耐药的横纹肌样肿瘤。
Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
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