The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.
The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.
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DOI：
10.1158/1078-0432.ccr-13-1110
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发表时间：
2013-12-15
期刊：
影响因子：
--
通讯作者：
Giaccone G
中科院分区：
文献类型：
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作者：
Lee JH;Park KS;Alberobello AT;Kallakury B;Weng MT;Wang Y;Giaccone G
小细胞肺癌(SCLC)预后较差，近二十年来对其内科治疗进展甚微。我们研究了Janus激酶(JAKs)抑制剂AZD1480在体内外治疗小细胞肺癌的可能性。用AZD1480或siRNAs抑制JAK1或JAK2，观察JAK基因家族抑制对小细胞肺癌细胞活力的影响。研究AZD1480对细胞周期分布和诱导细胞凋亡的影响。观察AZD1480在肿瘤移植瘤中的抗肿瘤作用。AZD1480可显著抑制6/13细胞的生长，IC50在0.73~3.08μM之间。AZD1480作用于小细胞肺癌细胞24小时后，4N DNA含量和组蛋白3丝氨酸10磷酸化水平增加，表现为G2/M期停滞。此外，AZD1480处理后的SCLC发生了凋亡，表现为MCL1表达下调，Caspase3断裂，PARP断裂，Annexin-V阳性细胞增多。最后，异种移植实验表明，AZD1480抑制了小鼠H82和GLC4肿瘤的生长，我们观察到AZD1480处理后H82和GLC4移植瘤中CD31阳性的内皮细胞减少，细胞凋亡率增加。Janus激酶抑制剂AZD1480在体内外抑制小细胞肺癌细胞的生长。小细胞肺癌抗JAKs治疗的临床进展值得进一步研究。
The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of janus kinases (JAKs) inhibitor AZD1480 for treatment of SCLC in vitro and in vivo. JAK1 or JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell cycle distribution and apoptosis induction were studied. Antitumor effects of AZD1480 in tumor xenografts were assessed. AZD1480 significantly inhibited growth of 6 out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μM. Knocking-down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in increase of 4N DNA content and Histone 3 serine 10 phosphorylation, indicative of G2/M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved-Caspase 3, cleaved PARP and increase of annexin-V positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31 positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment. Janus kinases inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.