山柰根茎乙醇提取物的抗胆管癌细胞活性和毒性。
Anticholangiocarcinoma activity and toxicity of the Kaempferia galanga Linn. Rhizome ethanolic extract.
机构信息
Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Phahonyothin Road, Klonglung District, Pathum Thani, 12120, Thailand.
出版信息
BMC Complement Altern Med. 2017 Apr 12;17(1):213. doi: 10.1186/s12906-017-1713-4.
BACKGROUND
Cholangiocarcinoma (CCA) is an important public health problem in several tropical and subtropical parts of the world particularly Thailand. Chemotherapy of CCA is largely ineffective and discovery and development of effective alternative drugs is urgently needed. The objective of the study was to confirm the anti-CCA potential as well as toxicity of the crude extract of Kaempferia galangal Linn. (rhizome) both in vitro and in animal models.
METHODS
The ethanolic extract of K. galanga Linn. rhizome, ethyl-p-methoxycinnamate (EPMC) and 5-fluorouracil (5-FU) were evaluated for their cytotoxic activities against CCA cell line (CL-6) using MTT cell proliferation assay. Acute and subacute toxicity of the extract were evaluated in ICR (Imprinting Control Region) mice according to the OECD (International Organization for Economic Co-operation and Development) Guideline. Anti-CCA activity was evaluated in CCA- xenografted nude mice.
RESULTS
Results of cytotoxicity test showed moderate activity of the extract and EPMC with median (95% confidence interval: 95% CI) 50% inhibitory concentration (IC) of 64.2 (57.76-72.11) and 49.19 (48.16-52.29) μg/ml, respectively. The IC of 5-FU was 107.1 (103.53-109.64) μg/ml. The selectivity index (SI) values for the extract, EPMC and 5-FU against human normal cell line (OUMS) and cancer cell line (CL-6) were 2.2, 2.09 and 1.31, respectively. Toxicity testing revealed no overt toxic effect up to the maximum single oral dose of 5000 mg/kg body weight and up to daily dose of 1000 mg/kg body weight for 30 days. The extract at the maximum tolerated dose level of 1000 mg/kg body weight for 30 days exhibited promising anti-CCA activity in CL6-xenografted nude mice as determined by inhibitory activity on tumor growth (58.41%) and lung metastasis (33.3%), as well as prolongation of survival time (62 days).
CONCLUSION
The K. galangal Linn. rhizome extract and its bioactive compound EPMC exhibited moderate cytotoxic activity against human CCA tumor (CL-6) cell line. Results of toxicity testing suggest that the extract was well tolerated up to the maximum single oral dose of 5000 mg/kg body weight and daily dose of 1000 mg/kg body weight for 30 days. The extract exhibited promising anti-CCA activity in CL6-xenografed nude mice as determined by significant inhibitory activity on tumor growth and lung metastasis, as well as prolongation of survival time.
背景
胆管癌（CCA）是世界上几个热带和亚热带地区的一个重要公共卫生问题，特别是在泰国。CCA 的化疗效果大多不佳，迫切需要发现和开发有效的替代药物。本研究的目的是在体外和动物模型中证实姜黄根茎的粗提取物以及乙基对甲氧基肉桂酸酯（EPMC）和 5-氟尿嘧啶（5-FU）的抗 CCA 潜力和毒性。
方法
采用 MTT 细胞增殖法测定姜黄根茎的乙醇提取物、EPMC 和 5-FU 对 CCA 细胞系（CL-6）的细胞毒性。根据 OECD（经济合作与发展组织）指南，在 ICR（印迹控制区）小鼠中评估提取物的急性和亚急性毒性。在 CCA 异种移植裸鼠中评估抗 CCA 活性。
结果
细胞毒性试验结果表明，提取物和 EPMC 具有中等活性，其 50%抑制浓度（IC）的中位数（95%置信区间：95%CI）分别为 64.2（57.76-72.11）和 49.19（48.16-52.29）μg/ml。5-FU 的 IC 为 107.1（103.53-109.64）μg/ml。提取物、EPMC 和 5-FU 对人正常细胞系（OUMS）和癌细胞系（CL-6）的选择性指数（SI）值分别为 2.2、2.09 和 1.31。毒性试验显示，最大单次口服剂量为 5000mg/kg 体重和最大日剂量为 1000mg/kg 体重，连续 30 天，无明显毒性作用。在 CL6 异种移植裸鼠中，提取物在最大耐受剂量水平（1000mg/kg 体重）下连续 30 天，表现出良好的抗 CCA 活性，表现为肿瘤生长抑制（58.41%）和肺转移抑制（33.3%）以及生存时间延长（62 天）。
结论
姜黄根茎提取物及其生物活性化合物 EPMC 对人 CCA 肿瘤（CL-6）细胞系表现出中等的细胞毒性活性。毒性试验结果表明，提取物在最大单次口服剂量为 5000mg/kg 体重和最大日剂量为 1000mg/kg 体重，连续 30 天内具有良好的耐受性。提取物在 CL6 异种移植裸鼠中表现出良好的抗 CCA 活性，表现为肿瘤生长和肺转移抑制以及生存时间延长。
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