5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBOSIDE ENHANCES EFFECT OF IONIZING RADIATION IN PC3 PROSTATE CANCER CELLS
5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBOSIDE ENHANCES EFFECT OF IONIZING RADIATION IN PC3 PROSTATE CANCER CELLS
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DOI：
10.1016/j.ijrobp.2011.06.1964
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发表时间：
2011-12-01
影响因子：
7
通讯作者：
Haustermans, Karin M.
中科院分区：
文献类型：
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作者：
Isebaert, Sofie F.;Swinnen, Johannes V.;Haustermans, Karin M.
目的：核苷5-氨基咪唑-4-甲酰胺核苷（AICAR）是一种低能量模拟物和腺苷一磷酸（AMP）激活的蛋白激酶（AMPK）激动剂，可通过降低恶性细胞的抗增殖性来影响其表型。它通过转化为5-氨基咪唑-4-甲酰胺核苷酸（ZMP），一种AMP类似物来实现这一点。我们结合了这一有前途的药物与电离辐射，试图增加其efficiency.Methods和材料：AICAR对细胞增殖，细胞活力，细胞凋亡，活性氧产生，放射敏感性，和AMPK激活的影响，在人前列腺癌细胞系PC 3。为了阐明放射增敏机制，在药物激动剂或拮抗剂或靶向AMPK的小干扰RNA存在下进行克隆形成存活测定，以及测量ZMP产生和双链断裂修复。此外，AICAR治疗后的辐射反应信号通路的免疫印迹分析performed.Results：人PC 3前列腺癌细胞与AICAR激活AMPK的孵育抑制细胞增殖，降低生存能力，增加凋亡，并产生活性氧在剂量和时间依赖性的方式。当加入辐射时，这些终点均没有超过累加效应。观察到放射增敏作用，但仅在用250 μ M AICAR处理72小时后才观察到，这表明它不依赖于AMPK活化。AMPK的小干扰RNA敲低证实了这一发现。放射增敏的机制与不平衡的脱氧核苷酸池由于ZMP积累AICAR管理后，干扰DNA repair.Conclusions：我们的研究结果之间的良好互动低剂量AICAR和电离辐射在PC 3细胞可以打开新的前景，为临床使用这种或类似的化合物。然而，仍然需要额外的研究来建立ZMP途径的普遍适用性。(C)2011 Elsevier Inc.
Purpose: The nucleoside 5-aminoimidazole-4-carboxamide riboside (AICAR) is a low-energy mimetic and adenosine monophosphate (AMP)-activated protein kinase (AMPK) agonist that can affect the phenotype of malignant cells by diminishing their anabolism. It does this by being converted to 5-aminoimidazole-4-carboxamide ribotide (ZMP), an AMP analog. We combined this promising antineoplastic agent with ionizing radiation in an attempt to increase its efficacy.Methods and Materials: The effect of AICAR on cell proliferation, cell viability, apoptosis, reactive oxygen species production, radiosensitivity, and AMPK activation was determined in the human prostate cancer cell line PC3. To elucidate the radiosensitizing mechanism, clonogenic survival assays in the presence of a drug agonist or antagonist or with small interfering RNA targeting AMPK were done, as well as measurements of ZMP production and double strand break repair. Moreover, immunoblot analysis of the radiation response signaling pathways after AICAR treatment was performed.Results: The incubation of human PC3 prostate cancer cells with AICAR-activated AMPK inhibited cell proliferation, decreased viability, increased apoptosis, and generated reactive oxygen species in a dose- and time-dependent manner. None of these endpoints gave more than additive effects when radiation was added. Radiosensitization was observed but only after 72 hours of treatment with 250 mu M AICAR, suggesting that it was independent of AMPK activation. This finding was confirmed by small interfering RNA knockdown of AMPK. The mechanism of radiosensitization was associated with imbalanced deoxynucleotide pools owing to ZMP accumulation after AICAR administration that interfered with DNA repair.Conclusions: Our findings on the favorable interaction between low doses of AICAR and ionizing radiation in PC3 cells could open new perspectives for the clinical use of this or similar compounds. However, additional research is still required to establish the ZMP pathway as being of general applicability. (C) 2011 Elsevier Inc.