Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects
Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects
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DOI：
10.1016/j.jep.2009.11.024
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发表时间：
2010-02-17
影响因子：
5.4
通讯作者：
Morimoto, Chikao
中科院分区：
文献类型：
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作者：
Otsuki, Noriko;Dang, Nam H.;Morimoto, Chikao
研究目的：番木瓜的不同部位。(CP)传统上被用作治疗包括癌症在内的许多疾病的民族药物。有一些晚期癌症患者在食用从CP叶中提取的茶叶提取物后获得缓解的轶事。然而，CP茶提取物的确切细胞作用机制仍不清楚。本研究的目的是研究水提物叶提取物对多种肿瘤细胞系生长的影响以及对人淋巴细胞的抗肿瘤作用。材料和方法：采用[H-3]-胸腺嘧啶核苷掺入法检测CP叶提取物对肿瘤细胞株和人外周血单个核细胞(PBMC)增殖反应的影响以及对PBMC的细胞毒活性。流式细胞仪分析和半胱氨酸天冬氨酸氨基转移酶-3/7活性检测证实其可诱导肿瘤细胞发生凋亡。采用酶联免疫吸附试验检测PBMC产生细胞因子的能力。结果：观察到CP提取物对肿瘤细胞有明显的生长抑制作用。在PBMC中，加入CP提取物后，IL-2和IL-4的产生减少，而IL-12p40、IL-12p70、干扰素-γ和肿瘤坏死因子-α的产生增加，但没有抑制生长。此外，CP提取物还能增强活化的PBMC对K562细胞的杀伤活性。此外，基因芯片分析表明，CP提取物的加入增强了23个免疫调节基因的表达，这些基因通过基因本体分析进行分类。在这方面，CCL2、CCL7、CCL8和SERPINB2是这些上调基因的代表，因此可以作为CP提取物免疫调节作用的指标。结果表明，番木瓜叶提取物具有抑制肿瘤细胞生长和刺激抗肿瘤作用的活性成分，其相对分子质量均小于1000。结论：番木瓜叶提取物可介导人体免疫系统Th1型转化，提示番木瓜叶提取物有可能用于治疗和预防癌症、各种变态反应性疾病等人类疾病，并可作为疫苗治疗的免疫佐剂。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
Aim of the study: Various parts of Carica papaya Linn. (CP) have been traditionally used as ethnomedicine for a number of disorders, including cancer. There have been anecdotes of patients with advanced cancers achieving remission following consumption of tea extract made from CP leaves. However, the precise cellular mechanism of action of CP tea extracts remains unclear. The aim of the present study is to examine the effect of aqueous-extracted CP leaf fraction on the growth of various tumor cell lines and on the anti-tumor effect of human lymphocytes. In addition, we attempted to identify the functional molecular weight fraction in the CP leaf extract.Materials and methods: The effect of CP extract on the proliferative responses of tumor cell lines and human peripheral blood mononuclear cells (PBMC), and cytotoxic activities of PBMC were assessed by [H-3]-thymidine incorporation. Flow cytometric analysis and measurement of caspase-3/7 activities were performed to confirm the induction of apoptosis on tumor cells. Cytokine productions by PBMC were measured by ELISA. Gene profiling of the effect of CP extract treatment was performed by microarray analysis and real-time RT-PCR.Results: We observed significant growth inhibitory activity of the CP extract on tumor cell lines. In PBMC, the production of IL-2 and IL-4 was reduced following the addition of CP extract, whereas that of IL-12p40, IL-12p70, IFN-gamma and TNF-alpha was enhanced without growth inhibition. In addition, cytotoxicity of activated PBMC against K562 was enhanced by the addition of CP extract. Moreover, microarray analyses showed that the expression of 23 immunomodulatory genes, classified by gene ontology analysis, was enhanced by the addition of CP extract. In this regard, CCL2, CCL7, CCL8 and SERPINB2 were representative of these upregulated genes, and thus may serve as index markers of the immunomodulatory effects of CP extract. Finally, we identified the active components of CP extract, which inhibits tumor cell growth and stimulates anti-tumor effects, to be the fraction with M.W. less than 1000.Conclusion: Since Carica papaya leaf extract can mediate a Th1 type shift in human immune system, our results suggest that the CP leaf extract may potentially provide the means for the treatment and prevention of selected human diseases such as cancer, various allergic disorders, and may also serve as immunoadjuvant for vaccine therapy. (C) 2009 Elsevier Ireland Ltd. All rights reserved.