Authors' Affiliations: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
Clin Cancer Res. 2013 Dec 15;19(24):6777-86. doi: 10.1158/1078-0432.CCR-13-1110. Epub 2013 Oct 24.
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-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo.
JAK1 and 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 was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed.
AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μmol/L. 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 an 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.
JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation.
小细胞肺癌（SCLC）的预后较差，在过去的二十年中，SCLC 的医学治疗几乎没有取得任何进展。我们研究了 Janus 激活激酶（JAK）抑制剂 AZD1480 治疗 SCLC 的潜力，包括体外和体内研究。
通过 AZD1480 或 siRNA 抑制 JAK1 和 JAK2，评估抑制 JAK 基因家族对 SCLC 细胞活力的影响。研究 AZD1480 对细胞周期分布和凋亡诱导的影响。评估 AZD1480 在肿瘤异种移植中的抗肿瘤作用。
AZD1480 显著抑制了 13 种 SCLC 细胞中的 6 种细胞的生长，IC50 范围为 0.73 至 3.08 μmol/L。敲低 JAK2 和 JAK1 分别抑制了 Jak2 阳性/Jak1 阴性 H82 细胞和 Jak1 阳性/Jak2 阴性 GLC4 细胞的增殖。用 AZD1480 处理 SCLC 细胞 24 小时后，导致 4N DNA 含量增加和组蛋白 3 丝氨酸 10 磷酸化，表明 G2-M 期阻滞。此外，SCLC 在用 AZD1480 处理后发生凋亡，表现为 MCL1 下调、cleaved caspase 3、cleaved PARP 积累和 Annexin-V 阳性细胞增加。最后，异种移植实验表明，AZD1480 减弱了 H82 和 GLC4 肿瘤在小鼠中的生长，并且我们观察到在 AZD1480 处理后 H82 和 GLC4 异种移植中的凋亡更强，以及 CD31 阳性内皮细胞减少。
JAK 抑制剂 AZD1480 减弱了 SCLC 细胞在体外和体内的生长。在 SCLC 中进一步研究抗-JAKs 治疗的临床开发是值得的。
