The role of reactive oxygen species and subsequent DNA-damage response in the emergence of resistance towards resveratrol in colon cancer models.
The role of reactive oxygen species and subsequent DNA-damage response in the emergence of resistance towards resveratrol in colon cancer models.
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DOI：
10.1038/cddis.2014.486
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发表时间：
2014-11-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管有治疗结肠癌的新策略，但与这种疾病相关的死亡率仍然居高不下。肿瘤复发与诱导对化疗产生耐药性有关，这种耐药性涉及使癌细胞能够逃脱细胞死亡的细胞事件。结肠癌的治疗主要涉及直接或间接的DNA损伤剂，对后续病变的修复或耐受性增加有助于产生耐药人群。白藜芦醇(RSV)是一种强大的化学增敏多酚，体外研究表明其间接DNA损伤作用可能与化疗药物具有共同的性质。在这项研究中，我们研究了RSV如何在结肠癌模型中发挥其抗癌作用，并特别强调了DNA损伤反应(DDR；PIKKs-CHKS-P53信号级联)及其细胞后果。我们在体外和体内证明，结肠癌模型可以逐渐逃脱RSV的重复药物治疗。我们首次观察到这种反应与DDR的瞬时激活、细胞凋亡和衰老有关。在体外，RSV单独处理诱导了与S期延迟和细胞凋亡相关的DDR，但长期处理会导致短暂的微核和与多倍体相关的衰老表型。最终，与亲本细胞相比，出现了对RSV表现出更高倍性和大核程度的稳定抗性群体。我们将这些瞬时效应和耐药性的产生与这些细胞逐渐逃避RSV诱导的DNA损伤的能力联系起来。最后，我们证明了这种DNA损伤是由癌细胞在长期暴露于RSV下能够适应的活性氧物种(ROS)的过度产生引发的。这项研究对RSV的长期影响进行了临床前分析，并强调了ROS是RSV间接DNA损伤特性的主要因素，以及在抗癌反应和强大耐药性出现方面的后果。
In spite of the novel strategies to treat colon cancer, mortality rates associated with this disease remain consistently high. Tumour recurrence has been linked to the induction of resistance towards chemotherapy that involves cellular events that enable cancer cells to escape cell death. Treatment of colon cancer mainly implicates direct or indirect DNA-damaging agents and increased repair or tolerances towards subsequent lesions contribute to generate resistant populations. Resveratrol (RSV), a potent chemosensitising polyphenol, might share common properties with chemotherapeutic drugs through its indirect DNA-damaging effects reported in vitro. In this study, we investigated how RSV exerts its anticancer effects in models of colon cancer with a particular emphasis on the DNA-damage response (DDR; PIKKs-Chks-p53 signalling cascade) and its cellular consequences. We showed in vitro and in vivo that colon cancer models could progressively escape the repeated pharmacological treatments with RSV. We observed for the first time that this response was correlated with transient activation of the DDR, of apoptosis and senescence. In vitro, a single treatment with RSV induced a DDR correlated with S-phase delay and apoptosis, but prolonged treatments led to transient micronucleations and senescence phenotypes associated with polyploidisation. Ultimately, stable resistant populations towards RSV displaying higher degrees of ploidy and macronucleation as compared to parental cells emerged. We linked these transient effects and resistance emergence to the abilities of these cells to progressively escape RSV-induced DNA damage. Finally, we demonstrated that this DNA damage was triggered by an overproduction of reactive oxygen species (ROS) against which cancer cells could adapt under prolonged exposure to RSV. This study provides a pre-clinical analysis of the long-term effects of RSV and highlights ROS as main agents in RSV's indirect DNA-damaging properties and consequences in terms of anticancer response and potent resistance emergence.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Elbling, L;Weiss, RM;Mickshe, M
通讯作者：
Mickshe, M
影响因子：
6.4
作者：
Harikumar, Kuzhuvelil B;Kunnumakkara, Ajaikumar B;Sethi, Gautam;Diagaradjane, Parmeswaran;Anand, Preetha;Pandey, Manoj K;Gelovani, Juri;Krishnan, Sunil;Guha, Sushovan;Aggarwal, Bharat B
通讯作者：
Aggarwal, Bharat B
影响因子：
5.2
作者：
Almeida, Luis;Vaz-da-Silva, Manuel;Soares-da-Silva, Patricio
通讯作者：
Soares-da-Silva, Patricio
影响因子：
24.3
作者：
Gordon, Ryan R.;Nelson, Peter S.
通讯作者：
Nelson, Peter S.