Autophagy inhibition improves the cytotoxic effects of receptor tyrosine kinase inhibitors.
Autophagy inhibition improves the cytotoxic effects of receptor tyrosine kinase inhibitors.
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DOI：
10.1186/s12935-018-0557-4
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发表时间：
2018
影响因子：
5.8
通讯作者：
Tonini GP
中科院分区：
文献类型：
--
作者：
Aveic S;Pantile M;Polo P;Sidarovich V;De Mariano M;Quattrone A;Longo L;Tonini GP
越来越多的证据表明致癌受体酪氨酸激酶（RTK）参与细胞转化。肿瘤中 RTK 活性的失调可以决定多种癌症的疾病进展和治疗反应，包括神经母细胞瘤 (NB)。因此，RTK 靶向对于肿瘤学家来说是一个值得挑战的挑战。然而，对 RTK 抑制剂（RTKi）的获得性耐药仍然是一个严重的问题。自噬激活是 RTKi 治疗取得良好疗效的可能障碍之一。在不同的处理条件下，我们使用免疫印迹和免疫荧光测定测量了自噬通量。通过台盼蓝排除测定和 FACS 分析（钙黄绿素-AM/碘化丙啶）验证死亡诱导。 NB细胞系SH-SY5Y和Kelly用于体外研究。为了确定自噬是否可能是 RTKi 在 NB 细胞中功效的限制因素，我们首先检查了几种 RTKi 处理后自噬的激活情况。接下来，我们研究了通过在体外将 RTKi 与自噬阻断剂相结合来提高其治疗效率的可能性。我们单独利用了三种 RTKi 或与自噬抑制剂（氯喹 - CQ 和 Spautin-1）联合使用的有效性。我们证明自噬诱导是药物依赖性的，并且它的抑制会不均匀地增加单个 RTKi 的抗肿瘤活性。我们观察到，联合使用损害晚期自噬事件的阻断剂（例如 CQ）和 RTKi 比单独使用 RTKi 更有效。在本报告中，我们评估了目前在 NB 临床前评估中使用不同 RTKi 时自噬被激活的条件。我们总结了 RTK/自噬抑制剂联合治疗的成就，认为这是增强 RTKi 损害肿瘤细胞活力的功效的一种有前途的方法。本文的在线版本 (10.1186/s12935-018-0557-4) 包含补充材料，可供授权用户使用。
A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in cell transformation. Deregulated activity of RTKs in tumors can determine disease progression and therapeutic responses in several types of cancer, including neuroblastoma (NB). Therefore, RTKs targeting is a worthwhile challenge for the oncologists. Nevertheless, acquired resistance to RTK inhibitors (RTKi) remains a serious problem. Autophagy activation is among the possible obstacles for good efficacy of the therapy with RTKi. Under different treatment conditions we measured autophagic flux using immunoblot and immunofluorescence assays. Death induction was validated by trypan blue exclusion assay and FACS analysis (calcein-AM/propidium iodide). The NB cell lines SH-SY5Y and Kelly were used for the in vitro study. In order to define whether autophagy might be a limiting factor for the efficacy of RTKi in NB cells, we firstly checked its activation following the treatment with several RTKi. Next, we investigated the possibility to increase their therapeutic efficiency by combining RTKi with autophagy blocking agents in vitro. We exploited the effectiveness of three RTKi either alone or in combination with autophagy inhibitors (Chloroquine—CQ and Spautin-1). We demonstrated that autophagy induction was drug-dependent, and that its inhibition increased the anti-tumor activity of a single RTKi unevenly. We observed that the combined use of blocking agents which impair late autophagy events, such as CQ, and RTKi can be more effective with respect to the use of RTKi alone. In the present report, we assessed the conditions under which autophagy is activated during the use of different RTKi currently in the pre-clinical evaluation for NB. We summarized the achievements of combined RTK/autophagy inhibitors treatment as a promising approach to enhance the efficacy of RTKi in impairing tumor cells viability. The online version of this article (10.1186/s12935-018-0557-4) contains supplementary material, which is available to authorized users.
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影响因子：
3.6
作者：
Fung, Christopher;Chen, Xing;Duvvuri, Umamaheswar
通讯作者：
Duvvuri, Umamaheswar
影响因子：
3.2
作者：
Donfrancesco, Alberto;De Ioris, Maria Antonietta;Dominici, Carlo
通讯作者：
Dominici, Carlo
影响因子：
11.2
作者：
Ho, R;Minturn, JE;Brodeur, GM
通讯作者：
Brodeur, GM
自噬与神经母细胞瘤的化学抗性有关。
影响因子：
3.8
作者：
Belounis A;Nyalendo C;Le Gall R;Imbriglio TV;Mahma M;Teira P;Beaunoyer M;Cournoyer S;Haddad E;Vassal G;Sartelet H
通讯作者：
Sartelet H
DOI：
10.1158/1541-7786.mcr-15-0477
发表时间：
2016-08
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Keller J;Nimnual AS;Varghese MS;VanHeyst KA;Hayman MJ;Chan EL
通讯作者：
Chan EL