Cytotoxic and radio-sensitizing effects of polyphenolic acetates in a human glioma cell line (BMG-1).
Cytotoxic and radio-sensitizing effects of polyphenolic acetates in a human glioma cell line (BMG-1).
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DOI：
10.2174/1381612820666140220112720
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发表时间：
2014-01
影响因子：
3.1
通讯作者：
A. Verma;Kavya Venkateswaran;A. Farooque;A. Bhatt;N. Kalra;A. Arya;A. Dhawan;M. B. Arya;H. Raj;A. Prasad;V. Parmar;B. Dwarakanath
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文献类型：
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作者：
A. Verma;Kavya Venkateswaran;A. Farooque;A. Bhatt;N. Kalra;A. Arya;A. Dhawan;M. B. Arya;H. Raj;A. Prasad;V. Parmar;B. Dwarakanath
背景和目的多酚乙酸酯（PAs）具有抗氧化/促氧化特性，也可以通过一种新的乙酰化药物——钙网蛋白转乙酰化酶乙酰化系统使蛋白质（酶）乙酰化。虽然PAs已被研究作为治疗多种疾病的药理学药物，但其作为抗癌药物的潜力或作为抗癌治疗的辅助药物的功效仍有待探索。在本研究中，我们研究了7,8 -二乙酰氧基-4-甲基香豆素（DAMC）和7-乙酰氧基-4-甲基香豆素（7- amc）对人胶质瘤细胞系（BMG-1）的细胞毒性和放射增敏作用。方法通过研究活性氧（ROS）水平、代谢活力、克隆生存、生长抑制、细胞周期扰动、DNA修复和细胞遗传损伤，以及组蛋白（H3）乙酰化分析，研究其细胞毒性和辐射致敏作用。结果细胞暴露于DAMC和7-AMC 24小时后，其毒性呈剂量依赖性增加，代谢活力、克隆存活和细胞增殖均降低，其中DAMC的毒性大于7-AMC。与7-AMC相比，DAMC的放射致敏程度也更高，这反映在克隆原性降低，辐射诱导的细胞周期扰动和凋亡增强。DAMC损害了辐射诱导的DNA双链断裂的去除（通过γH2AX免疫荧光测量），并增强了细胞遗传学损伤（微核形成），导致有丝分裂死亡增加。虽然DAMC单独诱导泛核γ - h2ax荧光，但DAMC +辐射联合处理同时观察到泛核和空间受限灶，表明DNA损伤和修复的复杂性。DAMC诱导的细胞毒性和辐射致敏作用独立于其促氧化活性，而组蛋白H3赖氨酸（9/14）超乙酰化似乎是一个潜在的靶标，调节细胞对电离辐射（IR）的反应。结论：多酚乙酸7,8 -二乙酰氧基-4-甲基香豆素（DAMC）在体外条件下具有抗癌作用和放射增敏潜力。
BACKGROUND AND AIMS Polyphenolic acetates (PAs) have antioxidant/ pro-oxidant properties and can also acetylate proteins (enzymes) by a novel acetoxy drug: calreticulin transacetylase acetylation system. While PAs have been investigated as pharmacological agents for the treatment of various diseases, their potential as anti-cancer agents or their efficacy as an adjuvant in anti-cancer therapeutics remains to be explored. In the present study we investigated the cytotoxic and radio-sensitizing effects of 7, 8- diacetoxy-4-methyl coumarin (DAMC) and 7- acetoxy-4-methyl coumarin (7-AMC) in a human glioma cell line (BMG-1). METHODS Cytotoxic and radio-sensitizing effects were investigated by studying reactive oxygen species (ROS) levels, metabolic viability, clonogenic survival, growth inhibition, cell cycle perturbation, DNA repair and cytogenetic damage, besides analyzing the histone (H3) acetylation. RESULTS Exposure of cells to DAMC and 7-AMC for 24 h showed a dose dependent increase in toxicity as indicated by reduced metabolic viability, clonogenic survival and cell proliferation, with DAMC being more toxic than 7-AMC. The degree of radiosensitization by DAMC was also higher as compared to 7-AMC as reflected by a decrease in the clonogenicity, enhanced radiation-induced cell cycle perturbation and apoptosis. DAMC impaired the removal of radiation-induced DNA double stranded breaks (measured by γH2AX immuno- fluorescence) and enhanced the cytogenetic damage (micronuclei formation), leading to an increase in mitotic death. While DAMC alone induced pan nuclear γH2AX fluorescence, both pan nuclear and spatially restricted foci was observed with the combined treatment (DAMC + Radiation) suggesting a complex nature of DNA damage and repair. DAMC- induced cytotoxic and radio-sensitizing effects were independent of its pro-oxidant activity, whereas histone H3 lysine (9/14) hyperacetylation appeared to be a potential target, regulating cellular responses to ionizing radiation (IR). CONCLUSIONS The polyphenolic acetate 7, 8- diacetoxy-4-methyl coumarin (DAMC) demonstrates both anticancer effects and radiosensitizing potential under in vitro conditions.