(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal
(S)-crizotinib reduces gastric cancer growth through oxidative DNA damage and triggers pro-survival akt signal
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(S)-克唑替尼通过氧化 DNA 损伤减少胃癌生长并触发促生存 akt 信号
DOI：
10.1038/s41419-018-0667-x
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发表时间：
2018-05-31
影响因子：
9
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Ji, Jiansong;Chen, Weiqian;Liang, Guang
胃癌是世界范围内常见的胃肠道恶性肿瘤，预后差，易复发。迫切需要确定胃癌的有效治疗方法。克唑替尼是一种多靶点、临床可用的口服酪氨酸激酶抑制剂，被批准用于肺癌，但其用于高度异质性的GC疾病尚不清楚。本研究的目的是探讨(S)-克里唑替尼抑制胃癌生长的抗癌机制。培养人GC细胞株（SGC-7901、BGC-823）和(S)-克里唑替尼耐药BGC-823/R，测定(S)-克里唑替尼对细胞活力、凋亡、氧化剂生成和细胞周期进程的影响。分别用药物阻断法检测ROS、Akt信号、MTH1和DNA损伤的参与情况。采用异种移植瘤小鼠，测定(S)-克里唑替尼的体内抗肿瘤作用。结果表明，(S)-克里唑替尼降低GC细胞活力，诱导生长停滞和凋亡，增加γ - h2ax和ser1981 -磷酸化的ATM的水平，而NAC可以抑制这些水平。(S)-克里唑替尼的抗癌机制不依赖于MTH1。此外，atm激活了促生存信号Akt，其抑制进一步增强了(S)-克里唑替尼诱导的异种移植小鼠GC细胞生长和肿瘤生长的抑制，并使耐药GC细胞对(S)-克里唑替尼重新敏感。(S)-crizotinib通过DNA氧化损伤机制抑制胃癌细胞和肿瘤生长，并触发促生存Akt信号。我们得出结论，(S)-克里唑替尼联合抑制Akt（阻断生存信号）可能为临床治疗胃癌提供一种有效的新型联合治疗方法。
Gastric cancer (GC), a common gastrointestinal malignancy worldwide, has poor prognosis and frequent recurrence. There is a great need to identify effective therapy for GC. Crizotinib is a multi-targeted, clinically available oral tyrosine kinase inhibitor approved for lung cancer, but its use for the highly heterogeneous disease of GC is unknown. The goal of this study was to investigate the anti-cancer mechanisms of the (S)-crizotinib in inhibiting GC growth. Human GC cell lines (SGC-7901 and BGC-823) and the (S)-crizotinib-resistant BGC-823/R were cultured for determining the effects of (S)-crizotinib on cell viability, apoptosis, oxidant generation, and cell cycle progression. Involvement of ROS, Akt signaling, MTH1, and DNA damage was tested with respective pharmacological blockade. The in vivo anti-tumor effects of (S)-crizotinib were determined using xenograft tumor mice. Results indicated that (S)-crizotinib decreased GC cell viability, induced growth arrest and apoptosis, and increased levels of γH2AX and Ser1981-phosphorylated ATM, which were inhibited by NAC. The anti-cancer mechanism of (S)-crizotinib was independent of MTH1. Moreover, ATM-activated Akt, a pro-survival signal, whose inhibition further enhanced (S)-crizotinib-induced inhibition of GC cell growth and tumor growth in xenograft mice, and re-sensitized resistant GC cells to (S)-crizotinib. (S)-crizotinib reduced GC cell and tumor growth through oxidative DNA damage mechanism and triggered pro-survival Akt signaling. We conclude that inclusion of Akt inhibition (to block the survival signaling) with (S)-crizotinib may provide an effective and novel combination therapy for GC in the clinical setting.