鞣花酸协同增强化疗药物对人肝癌细胞的抑制活性。
Ellagic acid synergistically potentiates inhibitory activities of chemotherapeutic agents to human hepatocellular carcinoma.
机构信息
College of Life Science, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
College of Life Science, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China.
出版信息
Phytomedicine. 2019 Jun;59:152921. doi: 10.1016/j.phymed.2019.152921. Epub 2019 Apr 4.
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.
背景
肝细胞癌（HCC）是预后最差的最常见恶性肿瘤之一。各种化疗药物用于 HCC 的治疗，但大多数对患者有显著的毒性。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。作为一种天然多酚，鞣花酸（EA）在癌症中表现出抑制作用。
目的
本研究旨在探讨 EA 的抗癌活性，重点研究其对 HCC 治疗中多柔比星盐酸盐（DOX）和顺铂（DDP）的刺激作用。
方法
用 EA、DOX、DDP 或它们的组合处理 HepG2、SMMC-7721 和 HL-7702 细胞。通过细胞活力和细胞凋亡实验来评估这些处理方法的细胞毒性。Western blot 分析和免疫荧光检测用于确定与线粒体凋亡途径相关的基因表达。为了评估 EA、DOX 和 EA+DOX 处理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，进行免疫组化和组织病理学评估。
结果
EA 可显著增强 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，EA 与相对低剂量的 DOX 联合有效地抑制了肿瘤生长，而没有观察到高剂量 DOX 治疗小鼠的心脏毒性。
结论
我们发现 EA 协同增强 DOX 和 DDP 抑制 HCC 的作用，同时显著降低副作用，这可能代表一种新的 HCC 治疗策略，具有高抗癌效率和低患者全身毒性。
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