Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo
Anti-tumor effect of AZD8055 against neuroblastoma cells in vitro and in vivo
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DOI：
10.1016/j.yexcr.2018.02.032
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发表时间：
2018-04-15
影响因子：
3.7
通讯作者：
Hirayama, Masahiro
中科院分区：
文献类型：
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作者：
Xu, Dong-Qing;Toyoda, Hidemi;Hirayama, Masahiro
神经母细胞瘤（NB）是儿童中最常见的实体瘤之一。尽管进行了全面和强化的治疗，高危 NB 仍然对约 50% 的患者致命。 PI3K/Akt/mTOR 信号通路的激活与 NB 的肿瘤发生、不良预后和化疗耐药相关。由于其在生长和代谢中的核心作用，mTOR 似乎是 NB 的一个重要因素，使其成为 NB 的可能靶点。在这项研究中，我们研究了 AZD8055（一种有效的 mTORC1-mTORC2 双重抑制剂）在 NB 细胞系中的作用。我们的数据表明 mTOR 信号传导在 NB 细胞中被广泛激活。在 AZD8055 处理的 NB 细胞中，mTOR 和下游分子的活性下调。值得注意的是，AZD8055 有效抑制 NB 细胞生长并诱导细胞周期停滞、自噬和凋亡。此外，AZD8055 显着降低小鼠异种移植模型中的肿瘤生长，且无明显毒性。总而言之，我们的结果凸显了 mTOR 作为 NB 治疗有希望的靶点的潜力。因此，AZD8055可在临床试验中进一步研究治疗高危NB。
Neuroblastoma (NB) is one of the most common solid tumors in children. High-risk NB remains lethal in about 50% of patients despite comprehensive and intensive treatments. Activation of PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis and chemotherapy resistance in NB. Due to its central role in growth and metabolism, mTOR seems to be an important factor in NB, making it a possible target for NB. In this study, we investigated the effect of AZD8055, a potent dual mTORC1-mTORC2 inhibitor, in NB cell lines. Our data showed that mTOR signaling was extensively activated in NB cells. The activity of mTOR and downstream molecules were down-regulated in AZD8055-treated NB cells. Significantly, AZD8055 effectively inhibited cell growth and induced cell cycle arrest, autophagy and apoptosis in NB cells. Moreover, AZD8055 significantly reduced tumor growth in mice xenograft model without apparent toxicity. Taken together, our results highlight the potential of mTOR as a promising target for NB treatment. Therefore, AZD8055 may be further investigated for treatment in clinical trials for high risk NB.