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首页> 美国卫生研究院文献>Molecular Pharmacology >The Chemopreventive Agent Curcumin Is a Potent Radiosensitizer of Human Cervical Tumor Cells via Increased Reactive Oxygen Species Production and Overactivation of the Mitogen-Activated Protein Kinase Pathway
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The Chemopreventive Agent Curcumin Is a Potent Radiosensitizer of Human Cervical Tumor Cells via Increased Reactive Oxygen Species Production and Overactivation of the Mitogen-Activated Protein Kinase Pathway

机译：化学预防剂姜黄素是人类宫颈肿瘤细胞的有效放射增敏剂其通过增加活性氧的产生和丝裂素活化的蛋白激酶途径的过度活化来实现。

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Cervical cancer is the second most common malignancy among women worldwide and is highly radioresistant, often resulting in local treatment failure. For locally advanced disease, radiation is combined with low-dose chemotherapy; however, this modality often leads to severe toxicity. Curcumin, a polyphenol extracted from rhizomes of the plant Curcuma longa, is a widely studied chemopreventive agent that was shown to have a low toxicity profile in three human clinical trials. Here, we show that pretreatment of two cervical carcinoma cell lines, HeLa and SiHa, with curcumin before ionizing radiation (IR) resulted in significant dose-dependent radiosensitization of these cells. It is noteworthy that curcumin failed to radiosensitize normal human diploid fibroblasts. Although in tumor cells, curcumin did not significantly affect IR-induced activation of AKT and nuclear factor-κB, we found that it caused a significant increase in the production of reactive oxygen species, which further led to sustained extracellular signal-regulated kinase (ERK) 1/2 activation. The antioxidant compound N-acetylcysteine blocked the curcumin-induced increased reactive oxygen species (ROS), sustained activation of ERK1/2, and decreased survival after IR in HeLa cells, implicating a ROS-dependent mechanism for curcumin radiosensitivity. Moreover, PD98059 (2′-amino-3′-methoxyflavone)-, PD184352- [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynylthio)butadiene]-specific inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) blocked curcumin-mediated radiosensitization, demonstrating that the sustained ERK1/2 activation resulting from ROS generation leads to curcumin-mediated radiosensitization. Together, these results suggest a novel mechanism for curcumin-mediated radiosensitization involving increased ROS and ERK1/2 activation and suggest that curcumin application (either systemically or topically) may be an effective radiation modifying modality in the treatment of cervical cancer.
机译：宫颈癌是全世界女性中第二大最常见的恶性肿瘤，具有很高的放射抵抗力，经常导致局部治疗失败。对于局部晚期疾病，放疗结合低剂量化疗。然而，这种方式经常导致严重的毒性。姜黄素是一种从植物姜黄的根茎中提取的多酚，是一项广泛研究的化学预防剂，在三项人类临床试验中均显示出低毒性。在这里，我们显示在电离辐射（IR）之前，用姜黄素预处理两种宫颈癌细胞系HeLa和SiHa会导致这些细胞的显着剂量依赖性放射增敏作用。值得注意的是，姜黄素未能使正常的人类二倍体成纤维细胞放射增敏。尽管姜黄素在肿瘤细胞中并没有显着影响IR诱导的AKT和核因子κB的活化，但我们发现它导致活性氧的产生显着增加，从而进一步导致持续的细胞外信号调节激酶（ERK） ）1/2激活。抗氧化剂化合物N-乙酰基半胱氨酸阻断了姜黄素诱导的HeLa细胞中活性氧（ROS）的增加，ERK1 / 2的持续活化以及IR后IR存活率的降低，这暗示了姜黄素放射敏感性的依赖于ROS的机制。另外，PD98059（2'-氨基-3'-甲氧基黄酮）-，PD184352- [2-（2-氯-4-碘-苯基氨基）-N-环丙基甲氧基-3,4-二氟苯甲酰胺]和U0126 [1丝裂原活化的蛋白激酶激酶1/2（MEK1 / 2）的[4,4-二氨基-2,3-二氰基-1,4-双（2-氨基菲硫基）丁二烯]特异性抑制剂可阻断姜黄素介导的放射增敏作用，表明ROS产生导致持续的ERK1 / 2活化导致姜黄素介导的放射增敏作用。在一起，这些结果表明姜黄素介导的放射增敏的新机制涉及增加的ROS和ERK1 / 2激活，并表明姜黄素的应用（全身或局部）可能是治疗宫颈癌的有效放射修饰方式。

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