关键词： Metastases Pancreatic neuroendocrine tumor Radiosensitization Radiotherapy Ribonucleotide reductase inhibitor

Mesh ： Humans Pancreatic Neoplasms / pathology radiotherapy genetics drug therapy enzymology Ribonucleoside Diphosphate Reductase / genetics antagonists & inhibitors metabolism Animals Cell Line, Tumor Radiation-Sensitizing Agents / pharmacology Apoptosis / drug effects Cell Proliferation / drug effects Xenograft Model Antitumor Assays Radiation Tolerance / drug effects Mice, Nude Phosphorylation Neuroendocrine Tumors / pathology genetics radiotherapy drug therapy enzymology metabolism Lung Neoplasms / secondary radiotherapy pathology genetics Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors metabolism genetics Tumor Suppressor Proteins / genetics metabolism Signal Transduction / drug effects Checkpoint Kinase 1 / antagonists & inhibitors metabolism genetics Mice Checkpoint Kinase 2 / metabolism genetics antagonists & inhibitors Female RNA Interference DNA-Activated Protein Kinase

来  源：   DOI：10.1016/j.canlet.2024.216993   PDF(Pubmed)

Abstract：
Ribonucleotide Reductase (RNR) is a rate-limiting enzyme in the production of deoxyribonucleoside triphosphates (dNTPs), which are essential substrates for DNA repair after radiation damage. We explored the radiosensitization property of RNR and investigated a selective RRM2 inhibitor, 3-AP, as a radiosensitizer in the treatment of metastatic pNETs. We investigated the role of RNR subunit, RRM2, in pancreatic neuroendocrine (pNET) cells and responses to radiation in vitro. We also evaluated the selective RRM2 subunit inhibitor, 3-AP, as a radiosensitizer to treat pNET metastases in vivo. Knockdown of RNR subunits demonstrated that RRM1 and RRM2 subunits, but not p53R3, play significant roles in cell proliferation. RRM2 inhibition activated DDR pathways through phosphorylation of ATM and DNA-PK protein kinases but not ATR. RRM2 inhibition also induced Chk1 and Chk2 phosphorylation, resulting in G1/S phase cell cycle arrest. RRM2 inhibition sensitized pNET cells to radiotherapy and induced apoptosis in vitro. In vivo, we utilized pNET subcutaneous and lung metastasis models to examine the rationale for RNR-targeted therapy and 3-AP as a radiosensitizer in treating pNETs. Combination treatment significantly increased apoptosis of BON (human pNET) xenografts and significantly reduced the burden of lung metastases. Together, our results demonstrate that selective RRM2 inhibition induced radiosensitivity of metastatic pNETs both in vitro and in vivo. Therefore, treatment with the selective RRM2 inhibitor, 3-AP, is a promising radiosensitizer in the therapeutic armamentarium for metastatic pNETs.
摘要：
核糖核苷酸还原酶（RNR）是脱氧核糖核苷三磷酸（dNTP）生产中的限速酶，它们是辐射损伤后DNA修复的重要底物。我们探索了RNR的放射增敏特性，并研究了一种选择性RRM2抑制剂，3-AP,作为治疗转移性pNETs的放射增敏剂。我们调查了RNR亚基的作用，RRM2，在胰腺神经内分泌（pNET）细胞中以及对体外辐射的反应。我们还评估了选择性RRM2亚基抑制剂，3-AP,作为体内治疗pNET转移的放射增敏剂。敲除RNR亚基表明RRM1和RRM2亚基，p53R3在细胞增殖中起重要作用。RRM2抑制通过ATM和DNA-PK蛋白激酶而不是ATR的磷酸化激活DDR途径。RRM2抑制也诱导Chk1和Chk2磷酸化，导致G1/S期细胞周期停滞。RRM2抑制使pNET细胞对放疗敏感并在体外诱导细胞凋亡。在体内,我们利用pNET皮下和肺转移模型来研究RNR靶向治疗和3-AP作为放射增敏剂治疗pNETs的基本原理.联合治疗显着增加BON（人pNET）异种移植物的凋亡，并显着减少肺转移的负担。一起,我们的结果表明，选择性RRM2抑制可在体内和体外诱导转移性pNETs的放射敏感性。因此,用选择性RRM2抑制剂治疗，3-AP,是一种有前途的放射增敏剂，用于转移性pNETs的治疗性医疗设备。
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