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Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy

机译：强力霉素下调DNA-PK并辐射致肿瘤细胞：对更有效放射治疗的意义

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DNA-PK is an enzyme that is required for proper DNA-repair and is thought to confer radio-resistance in cancer cells. As a consequence, it is a high-profile validated target for new pharmaceutical development. However, no FDA-approved DNA-PK inhibitors have emerged, despite many years of drug discovery and lead optimization. This is largely because existing DNA-PK inhibitors suffer from poor pharmacokinetics. They are not well absorbed and/or are unstable, with a short plasma half-life. Here, we identified the first FDA-approved DNA-PK inhibitor by “chemical proteomics”. In an effort to understand how doxycycline targets cancer stem-like cells (CSCs), we serendipitously discovered that doxycycline reduces DNA-PK protein expression by nearly 15-fold (> 90%). In accordance with these observations, we show that doxycycline functionally radio-sensitizes breast CSCs, by up to 4.5-fold. Moreover, we demonstrate that DNA-PK is highly over-expressed in both MCF7- and T47D-derived mammospheres. Interestingly, genetic or pharmacological inhibition of DNA-PK in MCF7 cells is sufficient to functionally block mammosphere formation. Thus, it appears that active DNA-repair is required for the clonal expansion of CSCs. Mechanistically, doxycycline treatment dramatically reduced the oxidative mitochondrial capacity and the glycolytic activity of cancer cells, consistent with previous studies linking DNA-PK expression to the proper maintenance of mitochondrial DNA integrity and copy number. Using a luciferase-based assay, we observed that doxycycline treatment quantitatively reduces the anti-oxidant response (NRF1/2) and effectively blocks signaling along multiple independent pathways normally associated with stem cells, including STAT1/3, Sonic Hedgehog (Shh), Notch, WNT and TGF-beta signaling. In conclusion, we propose that the efficacy of doxycycline as a DNA-PK inhibitor should be tested in Phase-II clinical trials, in combination with radio-therapy. Doxycycline has excellent pharmacokinetics, with nearly 100% oral absorption and a long serum half-life (18–22 hours), at a standard dose of 200-mg per day. In further support of this idea, we show that doxycycline effectively inhibits the mammosphere-forming activity of primary breast cancer samples, derived from metastatic disease sites (pleural effusions or ascites fluid). Our results also have possible implications for the radio-therapy of brain tumors and/or brain metastases, as doxycycline is known to effectively cross the blood-brain barrier. Further studies will be needed to determine if other tetracycline family members also confer radio-sensitivity.
机译：DNA-PK是正确修复DNA所必需的一种酶，被认为可以赋予癌细胞抗辐射性。因此，它是新药开发的备受验证的目标。然而，尽管有多年的药物发现和前导优化方法，但仍未获得FDA批准的DNA-PK抑制剂。这主要是因为现有的DNA-PK抑制剂的药代动力学较差。它们吸收不良和/或不稳定，血浆半衰期短。在这里，我们通过“化学蛋白质组学”鉴定了第一个FDA批准的DNA-PK抑制剂。为了了解强力霉素如何靶向癌干样细胞（CSC），我们偶然发现强力霉素将DNA-PK蛋白表达降低了近15倍（> 90％）。根据这些观察结果，我们显示强力霉素在功能上使乳腺CSC放射增敏多达4.5倍。而且，我们证明了DNA-PK在MCF7和T47D衍生的乳球体内都高度过量表达。有趣的是，MCF7细胞中DNA-PK的遗传或药理抑制作用足以在功能上阻止乳球形成。因此，看来CSCs的克隆扩增需要活性DNA修复。从机理上讲，多西环素治疗显着降低了癌细胞的氧化线粒体能力和糖酵解活性，这与先前将DNA-PK表达与线粒体DNA完整性和拷贝数的适当维持联系起来的研究一致。使用基于荧光素酶的分析，我们观察到强力霉素治疗可定量降低抗氧化反应（NRF1 / 2），并有效阻断通常与干细胞相关的多个独立途径的信号传导，这些途径包括STAT1 / 3，声波刺猬（Shh），Notch ，WNT和TGF-beta信号传导。总之，我们建议应在II期临床试验中结合放疗对多西环素作为DNA-PK抑制剂的功效进行测试。强力霉素具有出色的药代动力学，口服剂量接近200％，口服半衰期长（18-22小时），每天标准剂量为200 mg。为了进一步支持这一观点，我们证明了多西环素有效抑制了原发性乳腺癌样品的乳球形成活性，这些活性来源于转移性疾病部位（胸腔积液或腹水）。我们的研究结果也可能对脑肿瘤和/或脑转移瘤的放射治疗产生影响，因为已知强力霉素可有效地穿越血脑屏障。还需要进一步研究以确定其他四环素家族成员是否也具有放射敏感性。

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