Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD, USA.
Cancer Biol Ther. 2009 Dec;8(24):2386-95. doi: 10.4161/cbt.8.24.10184. Epub 2009 Dec 27.
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at < or =10 microM concentration. More interestingly, 17 compounds are active at < or =1 microM concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, eleven compounds are not currently used to treat NB. Among them, nine are FDA approved compounds, and three agents are undergoing clinical trials for various malignancies. Furthermore, we identified four agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic.
神经母细胞瘤（NB）是儿童最常见的颅外实体瘤。尽管目前采用了积极的治疗方法，高危 NB 的生存率仍低于 40%。为了鉴定针对 NB 的新型有效化疗药物，我们针对两种 NB 细胞系 SK-N-AS 和 SH-SY5Y 筛选了 96 种药物的组合。我们发现有 30 种化合物在 < 或 =10 microM 浓度下对 NB 细胞系具有活性。更有趣的是，有 17 种化合物在 < 或 =1 microM 浓度下具有活性，它们通过多种不同的机制发挥作用，如有丝分裂抑制、拓扑异构酶抑制、针对各种生物途径以及未知的机制。这些具有活性的化合物中的大多数还使 caspase 3/7 增加了 2 倍以上。在这些对 NB 细胞系具有亚微摩尔浓度活性的 17 种化合物中，有 11 种化合物目前不用于治疗 NB。其中，有 9 种是 FDA 批准的化合物，有 3 种药物正在针对各种恶性肿瘤进行临床试验。此外，我们还鉴定了对这些 NB 细胞系具有活性但尚未在临床环境中进行测试的四种药物。最后，我们证明葫芦素 I 通过抑制 STAT3 通路抑制神经母细胞瘤细胞的生长。这些药物因此代表了针对 NB 患者的潜在新型治疗剂，需要进一步的验证研究才能将其转化为临床应用。
