Alarcon-Vargas D, Zhang Z, Agarwal B, Challagulla K, Mani S, Kalpana G V
Department of Molecular Genetics, Albert Einstein College of Medicine, New York, NY, USA.
Oncogene. 2006 Feb 2;25(5):722-34. doi: 10.1038/sj.onc.1209112.
Rhabdoid tumors (RTs) are aggressive and currently incurable pediatric malignancies. INI1/hSNF5 is a tumor suppressor biallelically inactivated in RTs. Our previous studies have indicated that cyclin D1 is a key downstream target of INI1/hSNF5 and genesis and/or survival of RTs in vivo is critically dependent on the presence of cyclin D1. In this report, we have tested the hypothesis that therapeutic targeting of cyclin D1 is an effective means of treating RTs. We found that RNA interference of cyclin D1 in rhabdoid cells was sufficient to induce G1 arrest and apoptosis. Furthermore, we found that pharmacological intervention with low micromolar concentrations of N-(4-hydroxyphenyl)retinamide (4-HPR), which downmodulates cyclin D1, induced G1 arrest and apoptosis in rhabdoid cell lines. 4-HPR in combination with 4-hydroxy-tamoxifen (4OH-Tam), synergistically inhibited survival as well as anchorage-dependent and -independent growth of rhabdoid cells and caused synergistic induction of cell cycle arrest and apoptosis. 4-HPR and tamoxifen exhibited synergistic growth inhibition of RTs in xenograft models in vivo. The effects of combination of drugs were correlated to the depletion of cyclin D1 levels both in in vitro and in vivo tumor models. These results demonstrate that 4-HPR and tamoxifen are effective chemotherapeutic agents for RTs. We propose that downmodulation of cyclin D1 is a novel and effective therapeutic strategy for RTs.
横纹肌肉瘤（RTs）是侵袭性的儿科恶性肿瘤，目前无法治愈。INI1/hSNF5是一种在RTs中双等位基因失活的肿瘤抑制因子。我们之前的研究表明，细胞周期蛋白D1是INI1/hSNF5的关键下游靶点，RTs在体内的发生和/或存活严重依赖于细胞周期蛋白D1的存在。在本报告中，我们验证了靶向治疗细胞周期蛋白D1是治疗RTs的有效手段这一假设。我们发现，横纹肌样细胞中细胞周期蛋白D1的RNA干扰足以诱导G1期阻滞和凋亡。此外，我们发现用低微摩尔浓度的N-(4-羟基苯基)视黄酸（4-HPR）进行药物干预，可下调细胞周期蛋白D1，在横纹肌样细胞系中诱导G1期阻滞和凋亡。4-HPR与4-羟基他莫昔芬（4OH-Tam）联合使用，可协同抑制横纹肌样细胞的存活以及贴壁依赖性和非贴壁依赖性生长，并协同诱导细胞周期阻滞和凋亡。在体内异种移植模型中，4-HPR和他莫昔芬对RTs表现出协同生长抑制作用。在体外和体内肿瘤模型中，联合用药的效果与细胞周期蛋白D1水平的降低相关。这些结果表明，4-HPR和他莫昔芬是治疗RTs的有效化疗药物。我们提出，下调细胞周期蛋白D1是一种治疗RTs的新型有效治疗策略。
