Esomeprazole enhances the effect of ionizing radiation to improve tumor control.
Esomeprazole enhances the effect of ionizing radiation to improve tumor control.
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DOI：
10.18632/oncotarget.28008
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发表时间：
2021-07-06
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影响因子：
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通讯作者：
Ghebre YT
中科院分区：
文献类型：
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作者：
Hebert KA;Jaramillo S;Yu W;Wang M;Veeramachaneni R;Sandulache VC;Sikora AG;Bonnen MD;Annapragada AV;Corry D;Kheradmand F;Pandita RK;Ludwig MS;Pandita TK;Huang S;Coarfa C;Grimm SL;Perera D;Miles G;Ghebre YT
癌症细胞对放射治疗的耐药性是困扰癌症治疗标准的主要临床挑战。这个问题在许多实体瘤中尤其明显，因为这些肿瘤细胞对放射治疗只有部分反应。放射与放射增敏剂的结合能够增强肿瘤细胞的杀伤作用。然而，目前可用的放射增敏剂与显著的正常组织毒性有关。因此，开发更安全、更有效的放射增敏剂以改善肿瘤控制的需求尚未得到满足。在这里，我们在体外和HNSCC小鼠模型中评估了fda批准的药物埃索美拉唑对正常和放射耐药的人头颈部鳞状细胞癌（HNSCC）细胞的放射增敏作用。对于体外研究，我们使用癌细胞集落形成（克隆原性）测定来比较在没有或存在埃索美拉唑的情况下癌细胞的生长。为了确定作用机制，我们评估了细胞增殖和细胞周期调节蛋白。此外，我们还进行了逆相蛋白阵列（RPPA）研究，以了解埃索美拉唑对200多种癌症相关蛋白的整体影响。在体内研究中，我们将HNSCC移植到小鼠模型中，并比较了放疗、埃索美拉唑和放疗联合埃索美拉唑治疗动物的肿瘤生长情况。我们发现埃索美拉唑抑制肿瘤生长，并剂量依赖性地增强电离辐射对野生型和p53突变放射耐药癌细胞的杀伤作用。机制研究表明，埃索美拉唑通过上调p21蛋白和抑制细胞周期蛋白依赖性激酶（Cdks） 1型（Cdk1）和2型（Cdk2），在细胞周期的G1期抑制癌细胞。体内数据显示，与单独治疗相比，放射和埃索美拉唑联合治疗的动物肿瘤控制更好，这与体内细胞增殖抑制有关。此外，埃索美拉唑与辐射联合使用显著损害了辐射诱导的DNA损伤后的修复。我们的研究表明，埃索美拉唑使癌细胞对电离辐射敏感，并与p21的上调有关，从而使细胞处于细胞周期的G1期。我们的研究结果对于将埃索美拉唑重新用作HNSCC和其他实体肿瘤的放射增敏剂具有重要的治疗意义。
The resistance of cancer cells to radiation-based treatment is a major clinical challenge confounding standard of care in cancer. This problem is particularly notable in many solid tumors where cancer cells are only partially responsive to radiation therapy. Combination of radiation with radiosensitizers is able to enhance tumor cell killing. However, currently available radiosensitizers are associated with significant normal tissue toxicity. Accordingly, there is an unmet need to develop safer and more effective radiosensitizers to improve tumor control. Here, we evaluated the radiosensitizing effect of the FDA-approved drug esomeprazole in normal and radioresistant human head and neck squamous cell carcinoma (HNSCC) cells in vitro, and in a mouse model of HNSCC. For the in vitro studies, we used cancer cell colony formation (clonogenicity) assay to compare cancer cell growth in the absence or presence of esomeprazole. To determine mechanism(s) of action, we assessed cell proliferation and profiled cell cycle regulatory proteins. In addition, we performed reverse phase protein array (RPPA) study to understand the global effect of esomeprazole on over 200 cancer-related proteins. For the in vivo study, we engrafted HNSCC in a mouse model and compared tumor growth in animals treated with radiation, esomeprazole, and combination of radiation with esomeprazole. We found that esomeprazole inhibits tumor growth and dose-dependently enhances the cell killing effect of ionizing radiation in wildtype and p53-mutant radioresistant cancer cells. Mechanistic studies demonstrate that esomeprazole arrests cancer cells in the G1 phase of the cell cycle through upregulation of p21 protein and inhibition of cyclin-dependent kinases (Cdks) type 1 (Cdk1) and type 2 (Cdk2). In vivo data showed greater tumor control in animals treated with combination of radiation and esomeprazole compared to either treatment alone, and that this was associated with inhibition of cell proliferation in vivo. In addition, combination of esomeprazole with radiation significantly impaired repair following radiation-induced DNA damage. Our studies indicate that esomeprazole sensitizes cancer cells to ionizing radiation, and is associated with upregulation of p21 to arrest cells in the G1 phase of the cell cycle. Our findings have significant therapeutic implications for the repurposing of esomeprazole as a radiosensitizer in HNSCC and other solid tumors.