Ellagic acid synergistically potentiates inhibitory activities of chemotherapeutic agents to human hepatocellular carcinoma
Ellagic acid synergistically potentiates inhibitory activities of chemotherapeutic agents to human hepatocellular carcinoma
复制标题
鞣花酸协同增强化疗药物对人肝细胞癌的抑制活性
DOI：
10.1016/j.phymed.2019.152921
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发表时间：
2019-06-01
期刊：
影响因子：
7.9
通讯作者：
Sui, Guangchao
中科院分区：
文献类型：
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作者：
Zhong, Chen;Qiu, Shuang;Sui, Guangchao
背景：肝细胞癌（HCC）是最常见的恶性肿瘤之一，预后较差。多种化疗药物用于治疗HCC，但大多数对患者具有显着的毒性。因此，迫切需要开发新的治疗策略以实现高特异性和可耐受的不良反应。鞣花酸（EA）作为一种天然多酚，具有抑制癌症的作用。 目的：本研究的目的是研究 EA 的抗癌活性，重点关注其对 HCC 治疗中盐酸阿霉素（DOX）和顺铂（DDP）的刺激作用。方法：用 EA、DOX、DDP 或其组合处理 HepG2、SMMC-7721 和 HL-7702 细胞。检查细胞活力和细胞凋亡以评估这些治疗的细胞毒性。使用蛋白质印迹分析和免疫荧光测定来确定与线粒体凋亡途径相关的基因的表达。为了评估 EA、DOX 和 EA+ DOX 治疗的抗癌活性和全身毒性，采用接种 HepG2 细胞的异种移植小鼠模型，然后进行免疫组织化学和组织病理学评估。结果：EA 可以显着增强 DOX 和 DDP 对 HCC HepG2 和 SMMC-7721 细胞的抗癌活性，并降低其对正常肝 HL-7702 细胞的细胞毒性。 EA 及其与 DOX 或 DDP 的组合通过线粒体细胞色素 c 释放介导的途径诱导细胞凋亡。在裸鼠中，电针与相对低剂量的 DOX 组合可有效抑制肿瘤生长，且不会引起高剂量 DOX 治疗小鼠中观察到的心脏毒性。 结论：我们发现 EA 可以协同增强 DOX 和 DDP 抑制 HCC 的作用，同时显着降低副作用，这可能代表了 HCC 治疗的一种新策略，对患者具有高抗癌效率和低全身毒性。
Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with poor prognosis. Various chemotherapeutics are used in treatment of HCC, but most of them have significant toxicity to patients. Thus, it is urgently needed to develop new therapeutic strategies to achieve high specificity and tolerable adverse effects. As a natural polyphenol, ellagic acid (EA) demonstrates inhibitory effects in cancers.Purpose: The goal of the present study to investigate the anticancer activity of EA with a focus on its stimulating effects on doxorubicin hydrochloride (DOX) and cisplatin (DDP) in HCC treatment.Methods: HepG2, SMMC-7721 and HL-7702 cells were treated with EA, DOX, DDP or their combinations. Cell viability and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot analysis and immunofluorescent assays were used to determine expression of genes related to the mitochondrial apoptosis pathway. To assess the anticancer activities and systemic toxicity of EA, DOX and EA+ DOX treatments, a xenograft mouse model with inoculated HepG2 cells was employed, followed by immunohistochemical and histopathological evaluation.Results: EA could both markedly potentiate anticancer activities of DOX and DDP to HCC HepG2 and SMMC-7721 cells, and reduce their cytotoxicity to normal liver HL-7702 cells. EA and its combination with DOX or DDP induced cell apoptosis through a pathway mediated by mitochondrial cytochrome c release. In nude mice, EA combination with a relatively low dosage of DOX effectively inhibited tumor growth without causing cardiotoxicity observed in mice treated by a high dosage of DOX.Conclusion: We discovered that EA synergistically potentiated DOX and DDP in suppressing HCC with significantly reduced side effects and this may represent a novel strategy in HCC therapies with both high anticancer efficiencies and low systemic toxicity in patients.